WO2020257536A1 - Sélection de patient pour l'amélioration de l'immunité antitumorale chez des patients atteints d'un cancer - Google Patents

Sélection de patient pour l'amélioration de l'immunité antitumorale chez des patients atteints d'un cancer Download PDF

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WO2020257536A1
WO2020257536A1 PCT/US2020/038557 US2020038557W WO2020257536A1 WO 2020257536 A1 WO2020257536 A1 WO 2020257536A1 US 2020038557 W US2020038557 W US 2020038557W WO 2020257536 A1 WO2020257536 A1 WO 2020257536A1
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cancer
chemotherapy
inhibitor
patient
cdk4
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Patricks Joseph ROBERTS
Anne LAI
Jessica SORRENTINO
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G1 Therapeutics, Inc.
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Priority to JP2021575320A priority Critical patent/JP2022536854A/ja
Priority to AU2020296087A priority patent/AU2020296087A1/en
Priority to CN202080056941.0A priority patent/CN114222577A/zh
Priority to CA3143339A priority patent/CA3143339A1/fr
Priority to KR1020227001251A priority patent/KR20220024540A/ko
Priority to EP20825571.1A priority patent/EP3986410A4/fr
Publication of WO2020257536A1 publication Critical patent/WO2020257536A1/fr
Priority to US17/554,940 priority patent/US20220175787A1/en

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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • A—HUMAN NECESSITIES
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70539—MHC-molecules, e.g. HLA-molecules
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This invention is in the field of cancer therapy, and provides methods of selecting patients for advantageous and directed cancer treatment that includes the administration of a cyclin dependent kinase (CDK) 4/6 inhibitor in conjunction with chemotherapy, based on patient and cancer profiles as further described herein. It has been discovered that when a specified subsection of cancer patients is administered a CDK 4/6 inhibitor in conjunction with chemotherapy, this selected patient population exhibits a progression free survival benefit and/or an overall survival benefit. This result can in some embodiments be achieved without the use of an immune checkpoint inhibitor, such as an anti-PD-1, anti-PD-Ll, or anti-CTLA4 agent such as an antibody.
  • an immune checkpoint inhibitor such as an anti-PD-1, anti-PD-Ll, or anti-CTLA4 agent such as an antibody.
  • the tumor microenvironment consists of different cellular and non-cellular components in and around a tumor.
  • the TME has been recognized to play a significant role in tumor progression.
  • the TME shapes tumor evolution (whether the tumor regresses, develops resistance, evades the immune system and/or metastasizes) and consequently impacts patient outcomes. Chen et al., New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med. 2015 Mar 5; 13 :45. doi: 10.1186/sl2916-015-0278-7.
  • ICD immunological cell death
  • CTR calreticulin
  • HMGB1 high mobility group box 1
  • extracellular ATP extracellular ATP
  • type I interferon type I interferon
  • cancer cell- derived nucleic acids e.g., cancer cell- derived nucleic acids
  • Chemotherapeutic agents may also induce an immunogenic effect by disrupting strategies that tumors use to evade the immune response. See, e.g., Emens et al., The Interplay of Immunotherapy and Chemotherapy: Harnessing Potential Synergies. Cancer Immunol Res; 3(5) May 2015.
  • chemotherapy can modulate distinct features of tumor immunobiology in a drug-, dose-, and schedule-dependent manner, and distinct chemotherapy drugs may modulate the intrinsic immunogenicity of tumor cells through a variety of mechanisms (see, e.g., Chen G, Emens LA. Chemoimmunotherapy: reengineering tumor immunity. Cancer Immunol Immunother 2013;62:203-16.).
  • Chemotherapy can also enhance tumor antigen presentation by upregulating the expression of tumor antigens themselves, or of the MHC class I molecules to which the antigens bind.
  • chemotherapy may upregulate costimulatory molecules (B7-1) or downregulate coinhibitory molecules (PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, enhancing the strength of effector T-cell activity.
  • Chemotherapy may also render tumor cells more sensitive to T cell-mediated lysis through fas-, perforin-, and Granzyme B-dependent mechanisms.
  • T cells were found at the invasive margin but could not infiltrate (thus altered excluded), which allowed the tumor to protect itself.
  • tumors had a low degree of immune infiltration, which suggested a low degree of margin barriers but an immunosuppressed environment (thus altered immunosuppressed). This categorization of tumors is now becoming accepted in the field for not just colorectal cancer but also other cancers as a means to predict progression.
  • the category stratifications are based on type, density and location of immune cells within the tumor site (see FIG. 7a).
  • the authors classify tumors according to immune infiltration instead of cancer type, with a scoring system (“Immunoscore”) based on the quantification of two lymphocyte populations (CD3 and CD8) both at the tumor center and the invasive margin. The score ranges from 10 (low densities, such as absence of both cell types in both regions) to 14 (high immune cell types in both locations). 14 tumors are considered“hot” and 10 tumors are“cold”.
  • Tumor progression T stage
  • invasion N stage
  • Tumor progression T stage
  • N stage invasion
  • researchers are now looking at the nature, density, immune functional orientation, and distribution of immune cells in the tumor. See Galon, T, and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies’ Nature Reviews Drug Discovery (18), March 2019, 197-218.
  • the basic characteristics of hot immune tumors are (i) a high degree of T cell and cytotoxic T cell infiltration and (ii) checkpoint activation or impaired T-cell functions.
  • Altered-immunosuppressed immune tumors are categorized by (i) poor, but not absent, T-cell and cytotoxic T-cell infiltration, (ii) presence of soluble inhibitory mediators, (iii) the presence of immune suppressive cells and (iv) presence of T-cell checkpoints.
  • the characteristics of altered- excluded immune tumors are (i) no meaningful T cell infiltration inside the tumor and an accumulation of T cells at tumor borders, (ii) activation of oncogenic pathways, (iii) epigenetic regulation and reprogramming of the tumor microenvironment and (iv) aberrant tumor vasculature and/or stroma and (v) hypoxia.
  • the characteristics of a cold tumor are (i) absence of T cells within the tumor and at the tumor edges and (ii) failed T cell priming (i.e., poor, little or no antigen presentation, low tumor mutational burden and/or intrinsic insensitivity to T cell killing). Cold tumors can also show a low expression of PD-L1.
  • Galon et al. present a comprehensive wheel illustration of the four categories of tumors, the mechanisms used by the tumor cells to protect themselves, and the drugs/therapies that can be used to break through the protection.
  • Thorsson et al. identified six immune subtypes that encompass multiple tumor types based on extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types. See Thorsson et al.,“ The Immune Landscape of Cancer ,” Immunity 48, 812-830, 2018.
  • the six immune subtypes are: Cl -“Wound Healing” which is characterized by a high proliferation rate, high angiogenesis gene expression and a Th2 cell bias to the adaptive immune infiltrate; C2 -“IFN-g Dominant” which is characterized by the highest M1/M2 macrophage polarization, a strong CD8 signal and high TCR diversity; C3 -“Inflammatory,” which is characterized by elevated Thl7 and Thl genes, low to moderate proliferation, low aneuploidy and overall somatic copy number alterations; C4 -“Lymphocyte Depleted,” which is characterized by prominent macrophage signature with Thl suppression and high M2 response; C5 - “Immunologically Quiet,” which is characterized by a low lymphocyte response and a high macrophage response dominated by M2; and C6 -“TGF-b Dominant,” which is characterized by a mixed tumor subgroup with high TGF-b and lymphocytic infiltration.
  • T cell-inflamed GEP contained IFN-y-responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance, and these features were necessary, but not always sufficient, for attaining a clinical benefit from the use of a checkpoint inhibitor.
  • IFN-g Signature a subset of six genes
  • Expanded Immune Signature a further 18 genes whose expression profile provided a predictive value for determining the efficacy of PD-1 -/PD-L1 -directed monoclonal antibody treatment.
  • One goal is to be able to select the patient population for which the therapy may result in a progression free survival benefit and/or an overall survival benefit.
  • Another goal is to select a patient population for which therapy may result in a myelopreservation effect that protects immune cells, with or without a progression free survival or overall benefit, but with an enhanced patient experience or quality of life.
  • This invention addresses the problem of patient selection to achieve certain cancer therapy outcomes when the patient is administered a cyclin dependent kinas 4/6 inhibitor in combination with chemotherapy.
  • the tumor has is interferon-g (IFN-g) dominant according to Thorsson’ s Six Class Immune Signature, or a high IFN-g signature or expanded immune signature according to the Ayer’s IFN-g Signature Score or Expanded Immune Signature Score.
  • IFN-g interferon-g
  • the different specified subsection of cancer patients wherein a myelopreservation effect is achieved is not small cell lung carcinoma.
  • This patient population includes those with cancers that are not particularly immunogenic or sensitive to immune modulation, according to the characterizations as described in the Background or otherwise herein.
  • the cancer is poorly immunogenic and PD-L1 expression is relatively low (about less than 50%, 40% or even 30% that of normal expression).
  • the tumor has a reduced expression of major histocompatibility complex class I and class II molecules, a known immune escape mechanism, reflecting a less immunogenic environment.
  • This invention therefore provides a means to determine the outcome of therapy, and thus provides therapeutic protocols, using the appropriate selection of the combination of tumor type, chemotherapy type, and anti-cyclin dependent kinase (CDK) therapy and dosage regimen to maximize an anti-tumor immunity.
  • the benefit can be a reversal of T-cell exhaustion, enhancement of immune cell activation including T cells, the formation of immunological memory, and/or reduction of immunosuppression in addition to enhancing general immunosurveillance.
  • This result in some embodiments may be achieved without the use of an immune checkpoint inhibitor, such as an anti-PD-1, anti-PD-Ll or anti-CTLA4 agent such as an antibody.
  • the ability to extend progression free survival and/or overall survival without the need to administer a checkpoint inhibitor compound may reduce potential side-effects associated with immune checkpoint inhibitor treatments, including pneumonitis, hyperthyroidism, hypothyroidism, kidney infections, and immune-mediated rashes, including Stevens- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis, and bullous pemphigoid.
  • SJS Stevens- Johnson syndrome
  • TEN toxic epidermal necrolysis
  • exfoliative dermatitis bullous pemphigoid.
  • a cancer that is highly immunogenic for example, a hot tumor (as defined in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies’ supra, incorporated herein by reference and discussed further below)
  • high IFN-g expression, or other acceptable indicator of immunogenic susceptibility is treated with a chemotherapy that causes an immune-mediated response including, but not limited to, immunogenic cell death and/or regulatory T-cell (Treg cell) suppression, in combination with a short acting CDK4/6 inhibitor administered at least prior to the administration of the chemotherapy or alternatively, administered both prior to and concurrently with the chemotherapy.
  • the CDK4/6 inhibitor is further administered in a maintenance-type therapeutic regimen, wherein the CDK4/6 inhibitor is administered as a single agent without chemotherapy at a regular dosing, for example but not limited to, once a week, once every two weeks, once every three weeks, once a month, or once every six weeks following the completion of chemotherapy treatment.
  • the CDK4/6 inhibitor is further administered with the chemotherapeutic agent in a maintenance-type therapeutic regimen, wherein the CDK4/6 inhibitor is administered with a lower dose of chemotherapy at a regular dosing, for example but not limited to, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, once every five months, or once every six months following the completion of the initial chemotherapy treatment regimen.
  • progression free survival and/or overall survival can be improved when a cancer that is categorized as altered-excluded or altered immunosuppressed according to the Galon et al. scoring system is treated with a chemotherapy that enhances an immune mediated anti-tumor response, including but not limited to a chemotherapy that induces immunogenic cell death, in combination with a short acting CDK4/6 inhibitor administered at least prior to the administration of the chemotherapy, or alternatively administered both prior to and concurrently with the chemotherapy.
  • a chemotherapy that enhances an immune mediated anti-tumor response including but not limited to a chemotherapy that induces immunogenic cell death
  • the CDK4/6 inhibitor is further administered in a maintenance-type therapeutic regimen, wherein the CDK4/6 inhibitor is administered as a single agent without chemotherapy at a regular dosing, for example but not limited to, once a week, once every two weeks, once every three weeks, once a month, or once every six weeks following the completion of chemotherapy treatment.
  • the CDK4/6 inhibitor is further administered with the chemotherapeutic agent in a maintenance-type therapeutic regimen, wherein the CDK4/6 inhibitor is administered with a lower dose of chemotherapy at a regular dosing, for example but not limited to, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, once every five months, or once every six months following the completion of the initial chemotherapy treatment regimen.
  • the short acting CDK 4/6 inhibitor is selected from:
  • R is C(H)X, NX, C(H)Y, or C(X) 2, where X is straight, branched or cyclic Ci to Cs alkyl group, including methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, and cyclopentyl; and
  • Y is NR1R2 wherein Ri and R2 are independently X, or wherein Ri and R2 are alkyl groups that together form a bridge that includes one or two heteroatoms (N, O, or S);
  • two X groups can together form an alkyl bridge or a bridge that includes one or two heteroatoms (N, S, or O) to form a spiro compound, or a pharmaceutically acceptable salt thereof.
  • Cytotoxic chemotherapies generally do not differentiate between replicating healthy cells and cancer cells— killing both indiscriminately, including important stem cells in the bone marrow that produce white blood cells, red blood cells, and platelets.
  • This chemotherapy-induced bone marrow damage is known as myelosuppression.
  • white blood cells, red blood cells and platelets become depleted, patients receiving chemotherapy are at an increased risk of infection, experience anemia and fatigue, and are at an increased risk of bleeding.
  • Myelosuppression often requires the administration of rescue interventions such as growth factors and blood or platelet transfusions, and may also result in chemotherapy dose delays and reductions. It can also result in more hospital and doctor visits - burdening both the patient and the healthcare system, and increasing the risk to the patient.
  • a myelopreservation agent is one that preserves hematopoietic stem cells, white blood cells, red blood cells and/or platelets in a situation (such as chemotherapy) in which such cells would be otherwise stressed, damaged or killed.
  • Compound I also known as“trilaciclib” and developed by G1 Therapeutics, Inc., is currently being investigated in a number of human clinical trials for parenteral use as a myelopreservation agent administered via intravenous injection before chemotherapy with 1) gemcitabine and carboplatin in metastatic triple negative breast cancer (mTNBC), 2) topotecan in advanced staged small cell lung carcinoma (SCLC), 3) carboplatin and etoposide in SCLC, and 4) carboplatin, etoposide, and the PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq®) in SCLC.
  • mTNBC metastatic triple negative breast cancer
  • SCLC advanced staged small cell lung carcinoma
  • SCLC advanced staged small cell lung carcinoma
  • carboplatin and etoposide in SCLC and 4) carboplatin, etoposide, and the PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq®) in SCLC.
  • Compound III also known as “lerociclib” and developed by G1 Therapeutics, Inc., is currently being investigated in a number of human clinical trials as an antineoplastic agent, typically via continuous administration such as daily administration (with time off as necessary in the judgement of the healthcare provider) to treat 1) EGFR-mutant non-small cell lung carcinoma in combination with the EGFR inhibitor osimertinib (Tagrisso®), and 2) ER+, HER2- breast cancer in combination with fulvestrant.
  • EGFR-mutant non-small cell lung carcinoma in combination with the EGFR inhibitor osimertinib (Tagrisso®)
  • ER+, HER2- breast cancer in combination with fulvestrant.
  • trilaciclib or a pharmaceutically acceptable salt thereof, as the exemplary compound.
  • one of the other short acting CDK4/6 inhibitors described above may be used, including for example, lerociclib.
  • palbociclib, or another selective CDK 4/6 inhibitor such as abemaciclib or ribociclib is used. This is not a representation that any of these compounds are equivalent to trilaciclib in performance or effect, but instead, are considered alternative embodiments with potential alternative treatment effects, dosages or outcomes.
  • trilaciclib when used as a myelopreservation agent to treat small cell lung cancer, generally considered immunologically cold cancer— and thus less favorable to an induced immunological response— in combination with etoposide and carboplatin performed as designed, with a statistically significant myelopreservation effect, but not a statistically significant improvement in progression free survival or overall survival across the patient population.
  • Reviewing the clinical trial data indicates that within a sub-population of responders, significant immunological activity, most notably the expansion of new T-cell clones, was observed in those patients receiving trilaciclib (see Example 5, Figs. 11-14). Importantly, these same patients with observed increases in clonal expansion of T-cells also experienced increased overall survival.
  • the clinical data indicates that factors such as IFN-g signaling and the associated biology of T-cell cytolytic activity, antigen presentation, and chemokine production play a significant role in the anti -turn or efficacy of trilaciclib.
  • factors determining the potential effectiveness of CDK4/6 antitumor efficacy are measurable prior to the initiation of therapy, providing for an effective and reproducible determination of potential effectiveness and implementation of a therapeutic regimen capable of extending overall and/or progression free survival.
  • SCLC is characterized by a high degree of genomic instability and smoking-associated mutational profile
  • SCLC tumors have significantly reduced levels of both major histocompatibility complex class I and class II complexes, a known method of escaping antitumor immunity (which makes it an immunologically“cold-like” tumor) (Semenova et ak, Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev 2015; 29: 1447-62). Therefore, in SCLC, trilaciclib acts to reduce chemotherapy-induced myelosuppression, without necessarily improving on antitumor efficacy across the patient population.
  • TNBC is generally genomically unstable, and the tumor microenvironment may be more immunogenic or“hot-like” when treated with gemcitabine, a strong ICD-agent (see, e.g., Park et ak, How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies.
  • ESMO Open 2018; 3 (suppl 1): e000357) leading to improved antitumor efficacy and extended overall survival.
  • initial data cut-off showed a significant increase in median overall survival from 12.6 months with GC alone (Group 1 G/C therapy (Days 1 and 8 of 21-day cycles) 20.1 months (Group 2: G/C therapy (Days 1 and 8) plus trilaciclib administered IV on Days 1 and 8 of 21-day cycles;) and 17.8 months (Group 3 : G/C therapy (Days 2 and 9) plus trilaciclib administered IV on Days 1, 2, 8, and 9 of 21-day cycles) with the addition of trilaciclib (see Table 5; Fig. 2).
  • trilaciclib with certain tumor types and chemotherapeutic regimes is believed to enhance immune activation and promote antitumor immunity by differentially arresting cytotoxic and regulatory T cell subsets followed by a faster recovery of cytotoxic T lymphocytes (CTLs) compared with regulatory T cells (Tregs) in tumors.
  • CTLs cytotoxic T lymphocytes
  • Tregs regulatory T cells
  • This differential alteration of cell cycle kinetics between CTLs and Tregs results in a higher proportion of CTLs to Tregs, the enhancement of T-cell activation, and a decrease in Treg-mediated immunosuppressive functions. Together, these events promote the CTL-mediated clearance of tumor cells. Therefore, the anti-tumor effects of trilaciclib result from the transient proliferative arrest of T cells (protecting them from chemotherapy-induced damage), followed by activation of CTLs in the tumor microenvironment in the context of fewer Tregs.
  • T-cell receptor (TCR) analysis demonstrates that trilaciclib may play an important role in expanding anti-tumor T-cell subsets during treatment.
  • TCR T-cell receptor
  • trilaciclib significantly increased the number and fraction of newly expanded clones demonstrating that the addition of trilaciclib to the etoposide, carboplatin, atezolizumab treatment regimen enhances the T-cell mediated anti -turn or response.
  • the ability to extend overall survival in certain tumor types can be predicted prior to administration.
  • a statistically significant improvement in overall survival and progression free survival was observed in patients receiving trilaciclib whose TNBC was classified as C2 IFN-g Dominant according to the Thorsson et al.
  • Six Class Immune Signature classification system as defined in Thorsson et el., “The Immune Landscape of Cancer ,” supra, incorporated herein by reference and discussed further below
  • those patients with TNBC classified as C2 IFN-g Dominant who did not receive trilaciclib are considered in the Thorsson et al.
  • Example 3 a similar statistically significant improvement in overall survival and progression free survival was observed in patients who received trilaciclib whose TNBC had high “IFN-g Signature” and“Expanded Immune Signature” scores according to the Ayers et al. classification system (as defined in Ayers et al.,“Ib ' N-v related mRNA profile predicts clinical response to PD-1 blockade ,” supra, incorporated herein by reference and discussed further below) compared to patients with TNBC having a high“IFN-g Signature” and“Expanded Immune Signature” score and who did not receive trilaciclib. Furthermore, as described in Example 4, patients with TNBC PD-L1 positive tumors receiving trilaciclib had a significantly longer overall survival than patients with TNBC PD-L1 positive tumors who did not receive trilaciclib.
  • the inclusion of a CDK4/6 inhibitor described herein in combination with a chemotherapeutic that enhances an immune-mediated response can be used to treat CDK4/6-replication dependent tumors, CDK4/6 replication-independent tumors, or a heterogeneous tumor with both CDK4/6 dependent and independent cells, wherein the tumor is hot, or in alternative embodiments, altered immunosuppressive or altered excluded.
  • a CDK4/6 inhibitor described herein in combination with a chemotherapeutic can be used to treat CDK4/6-replication dependent tumors, CDK4/6 replication-independent tumors, or a heterogeneous tumor with both CDK4/6 dependent and independent cells, wherein the tumor is immunogenic, for example determined to: be immunogenically hot; have a high Immunoscore, for example an Immunoscore of 14; be C2“IFN- g Dominant;” have a high“IFN-g Signature” or“Expanded Immune Signature” score; be PD-L1 positive; or be immunogenic as determined by any other recognizable assessment known in the art.
  • a chemotherapeutic for example an ICD-inducing chemotherapeutic
  • a method for selecting a patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising:
  • the increase in progression free survival and/or overall survival is in comparison to the predicted overall survival based on administration of the chemotherapy alone, either based on literature or otherwise publicly available evidence, a comparative during preclinical or clinical trials, or other means accepted by persons skilled in the field.
  • the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I antigens available to initiate an immune effect. In some embodiments, the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class II antigens available to initiate an immune effect. In some embodiments, the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I and class II antigens available to initiate an immune effect.
  • the patient has a cancer that is classified as immunogenic. In some embodiments, the patient has a cancer that is classified as hot, as described herein. In some embodiments, the patient has a cancer that is classified as altered-excluded, as described herein. In some embodiments, the patient has a cancer that is classified as a C2“IFN-g Dominant” class cancer, as described herein. In some embodiments, the patient has a cancer that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature,” as described herein. In some embodiments, the patient has a cancer that is PD-L1 positive.
  • the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound II, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound IV, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound V, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor is administered about 24 hours or less prior to the administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy.
  • the CDK4/6 inhibitor is administered about 4 hours or less prior to the administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy. In some embodiments, the CDK4/6 inhibitor is administered about 30 minutes or less prior to administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy. In some embodiments, the CDK4/6 inhibitor is administered first between about 18 to 28 hours prior to administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy, and again about 4 hours or less prior to administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy. In some embodiments, the patient is not administered an immune checkpoint inhibitor.
  • the CDK4/6 inhibitor is administered one or more times following the completion of chemotherapy treatment in a maintenance treatment regime, for example, once a week, once every two weeks, once every three weeks, once a month, once every six months.
  • the CDK4/6 inhibitor is administered in combination with the chemotherapeutic one or more times following the completion of treatment in a chemotherapy dose reduced maintenance treatment regime, for example, at least once a week, at least once every two weeks, at least once every three weeks, at least once a month, at least once every six weeks, at least once every two months, at least once every three months, at least once every four months, at least once every five months, or at least once every six months.
  • a method for selecting a patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising: :
  • the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment and that a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or Compound V, or pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with the administration of the chemotherapy and, wherein the improvement in progression free survival and/or overall survival is in comparison to the progression free survival and/or overall survival based on administration of the chemotherapy alone, either based on literature or otherwise publicly available evidence, a comparative during preclinical or clinical trials, or other means accepted by persons skilled in the field.
  • a chemotherapy that induces an immune-response for example an ICD-inducing chemotherapy
  • the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I antigens available to initiate an immune effect. In some embodiments, the determination of whether the cancer is immunogenically susceptible to CDK 4/6 inhibitor treatment comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class II antigens available to initiate an immune effect. In some embodiments, the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I and class II antigens available to initiate an immune effect.
  • the patient has a cancer that is classified as immunogenic. In some embodiments, the patient has a cancer that is classified as hot, as described herein. In some embodiments, the patient has a cancer that is classified as altered-excluded, as described herein. In some embodiments, the patient has a cancer that is classified as a C2“IFN-g Dominant” class cancer, as described herein. In some embodiments, the patient has a cancer that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature,” as described herein. In some embodiments, the patient has a cancer that is PD-L1 positive.
  • the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound II, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound IV, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor administered is Compound V, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor is administered about 24 hours or less prior to the administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy.
  • the CDK4/6 inhibitor is administered about 4 hours or less prior to the administration of the immune-response mediating chemotherapy, for example, an ICD inducing chemotherapy. In some embodiments, the CDK4/6 inhibitor is administered about 30 minutes or less prior to administration of the immune-response mediating chemotherapy, for example, an ICD-inducing chemotherapy. In some embodiments, the CDK4/6 inhibitor is administered first about 22 to 26 hours prior to administration of the immune-response mediating chemotherapy, for example, an ICD-inducing chemotherapy, and again about 4 hours or less prior to administration of the immune-response mediating chemotherapy, for example, an ICD-inducing chemotherapy. In some embodiments, the patient is not administered an immune checkpoint inhibitor.
  • the CDK4/6 inhibitor is administered one or more times following the completion of chemotherapy treatment in a maintenance treatment regime, for example, once a week, once every two weeks, once every three weeks, once a month, once every six months.
  • the CDK4/6 inhibitor is administered in combination with the chemotherapeutic one or more times following the completion of treatment in a chemotherapy dose reduced maintenance treatment regime, for example, at least once per week, at least once every two weeks, at least once every three weeks, at least once a month, at least once every two months, at least once every six weeks, at least once every three months, at least once every four months, at least once every five months, or at least once every six months.
  • Chemotherapies capable of inducing an immune-mediated responses include, but are not limited to, alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitroxantrone, gemcitabine, and 5-fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes, such as paclitaxel cabazitaxel, and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan, and etoposide; platinum compounds such as carboplatin and cisplatin; bortezomib, an inhibitor of the 26S proteasome subunit; vinca alkal
  • the ICD-inducing chemotherapy is selected from idarubicin, epirubicin, doxorubicin, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, and combinations thereof.
  • the targeted cancers suitable for the treatment using the presently described methods with a CDK 4/6 inhibitor include those tumors that are immunogenic or susceptible to an immuno- oncology chemotherapeutic treatment regimen.
  • the patient to be treated has an immunogenic cancer selected from the group consisting of breast cancer, including estrogen receptor (ER)-positive breast cancer, triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), diffuse large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumors, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, endometrial cancer, cholangiocarcinoma, hepatocellular carcinoma, Merkel cell carcinoma
  • methods provided herein include:
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising: (i) determining if the cancer has a surrounding microenvironment that is favorable to immune modulation; (ii) determining whether the chemotherapy regimen induces a immune-mediated response such as immunogenic cell death, and (iii) if both (i) and (ii) are yes, administering an effective amount of a CDK4/6 inhibitor selected from Compounds I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to the administration of the chemotherapy or optionally prior to and concurrently with chemotherapy; and, wherein the increase in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone, either based on literature or otherwise publicly available evidence, a comparative during preclinical or clinical trials, or other means accepted by persons skilled in the field.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising: (i) determining the immunogenic classification of the cancer; (ii) determining whether the patient can be administered a chemotherapy capable of inducing an immune-mediated response, for example an ICD-inducing chemotherapy, based on the cancer; and, (iii) if it is determined a chemotherapy capable of inducing an immune-mediated response, for example an ICD-inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or Compound V or pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapy or optionally prior to and concurrently with chemotherapy, and wherein the improvement in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising: (i) determining whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment; (ii) determining whether the patient can be administered a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, based on the cancer; (iii) and, if it is determined that the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment and that a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or Compound V, or pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising: (i) determining whether the cancer is immunogenic; (ii) determining whether the patient can be administered a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, based on the cancer; (iii) and, if it is determined that the cancer is immunogenic and that a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or Compound V, or pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with the administration of the chemotherapy, and wherein the improvement in progression free survival or overall survival
  • a compound selected from Compound I, Compound II, Compound III, Compound IV, Compound V, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for cancer therapy to a selected patient or patient population in a manner that increases the progression free survival or overall survival of the patient or patient population comprising: (i) determining if the cancer has a surrounding microenvironment that is favorable to immune modulation; (ii) determining if the chemotherapy regimen induces an immune-mediated response such as immunogenic cell death, and (iii) if both (i) and (ii) are yes, administering an effective amount of a CDK4/6 inhibitor selected from Compounds I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to the administration of the chemotherapy or optionally prior to and concurrently with chemotherapy; and, wherein the increase in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone, either based on literature or otherwise publicly available
  • a compound selected from Compound I, Compound II, Compound III, Compound IV, Compound V, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for cancer therapy to a selected patient or patient population in a manner that increases the progression free survival or overall survival of the patient or patient population comprising; (ii) determining whether the patient can be administered a chemotherapy capable of inducing an immune-mediated response, for example an ICD-inducing chemotherapy, based on the cancer; and, (iii) if it is determined a chemotherapy capable of inducing an immune-mediated response, for example an ICD-inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or Compound V or pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to administration of the chemotherapy or optionally prior to and concurrently with chemotherapy, and wherein the improvement in progression free survival or overall
  • the patient is not administered a check-point inhibitor in during the treatment regimen.
  • G. Use of a compound selected from Compound I, Compound II, Compound III, Compound IV, Compound V, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for cancer therapy to a selected patient or patient population in a manner that increases the progression free survival or overall survival of the patient or patient population comprising: (i) determining whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment; (ii) determining whether the patient can be administered a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, based on the cancer; (iii) and, if it is determined that the cancer is immunogenically susceptible to CDK 4/6 inhibitor treatment and that a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I
  • a compound selected from Compound I, Compound II, Compound III, Compound IV, Compound V, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for cancer therapy to a selected patient or patient population in a manner that increases the progression free survival or overall survival of the patient or patient population comprising: (i) determining whether the cancer is immunogenic; (ii) determining whether the patient can be administered a chemotherapy that induces an immune-response, for example an ICD-inducing chemotherapy, based on the cancer; (iii) and, if it is determined that the cancer is immunogenic and that a chemotherapy that induces an immune-response, for example an ICD- inducing chemotherapy, can be administered, administering an effective amount of the chemotherapy in combination with an effective amount of a short-acting CDK4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or Compound V, or pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to administration of the
  • Fig. 1 is a study schematic of G1T28-04 human clinical trial assessing the clinical benefit of trilaciclib (Compound I) in preserving the bone marrow and the immune system, and enhancing chemotherapy antitumor efficacy when administered prior to carboplatin and gemcitabine (GC therapy) for patients with metastatic triple negative breast cancer (mTNBC).
  • the treatment phase consisted of 21-day cycles: Trilaciclib was administered intravenously prior to gemcitabine/carboplatin infusions at 240mg/m 2 . Gemcitabine was administered via IV at 1000mg/m 2 . Carboplatin was administered IV at a calculated dose based on an area under the curve (AUC) of 2 for each patient. Peripheral blood samples were collected predose and on Day
  • Fig. 2 is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21-day cycles), Group
  • Fig. 3 is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21-day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle).
  • the x-axis depicts months from randomization and number of patients at risk.
  • the y-axis depicts the probability of being progression free. Data cut-off date May 15, 2020.
  • Fig. 4A is a Forest plot of overall survival in triple negative breast cancer human patients from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 -day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle). Data are from the intention to treat population and data from trilaciclib groups 2 and 3 were pooled for prespecified subgroup analysis.
  • Acquired triple-negative breast cancer refers to a patient with confirmed metastatic triple negative breast cancer and any previous biopsy showing estrogen and progesterone receptor or HER2 positivity.
  • Fig. 4B is a Forest plot of progression free survival in triple negative breast cancer human patients from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21-day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle).
  • Data are from the intention to treat population and data from trilaciclib groups 2 and 3 were pooled for prespecified subgroup analysis.
  • Acquired triple-negative breast cancer refers to a patient with confirmed metastatic triple negative breast cancer and any previous biopsy showing estrogen and progesterone receptor or HER2 positivity.
  • Fig. 4C is a Forest plot of overall survival in triple negative breast cancer human patients from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 -day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle). Data are from the intention to treat population and data from trilaciclib groups 2 and 3 were pooled for prespecified subgroup analysis.
  • Acquired triple-negative breast cancer refers to a patient with confirmed metastatic triple negative breast cancer and any previous biopsy showing estrogen and progesterone receptor or HER2 positivity.
  • Fig. 4D is a Forest plot of progression free survival in triple negative breast cancer human patients from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21-day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle).
  • Data are from the intention to treat population and data from trilaciclib groups 2 and 3 were pooled for prespecified subgroup analysis.
  • Acquired triple-negative breast cancer refers to a patient with confirmed metastatic triple negative breast cancer and any previous biopsy showing estrogen and progesterone receptor or HER2 positivity.
  • Fig. 5 is a graph showing the normalized mean frequency of interferon-gamma (IFN-g) + population of CD8+ T cells after ex vivo stimulation (IFN-g + IL-17A-[CD3+CD8+]).
  • Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21-day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle).
  • Fig. 6 is a reproduction of figure 3 found in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies , Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety, describing an immunogram for use as a tool to direct anticancer therapy. Cancers can be classified into four main subtypes (hot, altered- excluded, altered- immunosuppressed and cold) according to their associated T cell (CD3+ and CD8+) presence and distribution.
  • Hot cancers are defined by the simultaneous presence of immune contexture parameters: the cell type (CD3+, CD8+, follicular helper T (TFH), T helper 1 (TH1), memory and exhausted T cells); the location (invasive margin, tumor core and tertiary lymphoid structures); the density (immune density and quantity); and the functional immune orientation (chemokines, cytokines, cytotoxic factors, adhesion, attraction and TH1).
  • TSH follicular helper T
  • TH1 T helper 1
  • memory and exhausted T cells the location (invasive margin, tumor core and tertiary lymphoid structures); the density (immune density and quantity); and the functional immune orientation (chemokines, cytokines, cytotoxic factors, adhesion, attraction and TH1).
  • DORA2A A2A adenosine receptor
  • b m b2- microglobulin
  • BET bromodomain and extra-terminal motif proteins
  • BTLA B and T lymphocyte attenuator
  • CAR T-cell chimeric antigen receptor T-cell
  • CCR CC-chemokine receptor
  • CIN chromosomal instability, CSF1R, colony-stimulating factor 1 receptor
  • CTL A4 cytotoxic T lymphocyte-associated antigen
  • CXCL CXC-chemokine ligand
  • DDR DNA damage response
  • ECM extracellular matrix
  • EMT epithelial-mesenchymal transition
  • FDA US Food and Drug Administration
  • GITR glucocorticoid-induced TNFR-related protein
  • GM-CSF granulocyte-macrophage colony- stimulating factor
  • HD AC histone
  • Fig. 7A is a reproduction of Fig. 1 A found in Galon, L, and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies , Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety, which illustrates examples of hot, altered and cold immune cancers.
  • Dark (3,3'-diaminobenzidine (DAB)) staining represents CD3+ T cells and lighter (alkaline phosphatase) counterstaining provides homogeneous tissue background staining.
  • CD3+ and CD8+ T cell infiltration differentiates four distinct solid tumor phenotypes: hot (or inflamed); altered, which can be excluded or immunosuppressed; and cold (or non- inflamed). These tumor phenotypes are characterized by high, intermediate, and low immunoscore, respectively.
  • Fig. 7B is a reproduction of Fig. IB found in Galon, L, and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies , Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety, which is a schematic representation of the four subtypes of immune tumor.
  • CD3+ and CD8+ T cell infiltrates are low at the tumor center and high at the invasive margin, resulting overall in an intermediate immunoscore.
  • Altered- immunosuppressed tumors display instead a more uniform pattern of (low) CD3+ and CD8+ T cell infiltration.
  • CT center of tumor
  • Hi high
  • IM invasive margin
  • Lo low.
  • Fig. 8A is a schematic of the distribution of Ayers’ IFN-g Signature scores from pre treatment cancer samples from patients participating in the G1T28-04 clinical trial (NCT02978716).
  • the x-axis represents the probability density curve, and the y-axis is the calculated Ayers’ IFN-g Signature score.
  • the vertical dash line on the left side of the graph represents tertile 1
  • the vertical dash line on the right side of the graph represents tertile 2
  • the vertical dash line between tertile 1 and tertile 2 represents the median.
  • Fig. 8B is a schematic of the distribution of Ayers’ Expanded Immune Signature scores from pre-treatment cancer samples from patients participating in the G1T28-04 clinical trial (NCT02978716).
  • the x-axis represents the probability density curve
  • the y-axis is the calculated Ayers’ IFN-g Signature score.
  • the vertical dash line on the left side of the graph represents tertile 1
  • the vertical dash line on the right side of the graph represents tertile 2
  • the vertical dash line between tetile 1 and tertile 2 represents the median.
  • Fig. 8C is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients in G1T28-04 clinical trial (NCT02978716) from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21-day cycle), and Group 4 (Group 2 + Group 3) determined to have a high Ayers’ IFN-g Signature score.
  • the x-axis depicts months from randomization.
  • Fig. 8D is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients in G1T28-04 clinical trial (NCT02978716) from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a low Ayers’ IFN-g Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive.
  • Fig. 8E is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a low Ayers’ IFN-g Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2; _ Group 3;
  • Fig. 8F is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a low Ayers’ IFN-g Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2; _ Group 3;
  • Fig. 9A is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a high Ayers’ Expanded Immune Signature score.
  • the x-axis depicts months from randomization.
  • Fig. 9B is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a low Ayers’ Expanded Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2; _ Group 3;
  • Fig. 9C is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a high Ayers’ Expanded Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2; _ Group 3;
  • Fig. 9D is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a low Ayers’ Expanded Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive Legend: _ Group 1; - Group 2; _ Group 3;
  • Fig. 10A is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a C2 IFN-g Dominant Six Class Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Overall survival was significantly longer for Group 4
  • Fig. 1 OB is a Kaplan-Meier plot of overall survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21-day cycle), and Group 4 (Group 2 + Group 3) determined to have a non-C2 IFN-g Dominant Six Class Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2; _ Group 3;
  • Fig. IOC is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have C2 IFN-g Dominant Six Class Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2;
  • Fig. 10D is a Kaplan-Meier plot of progression free survival of triple negative breast cancer human patients in G1T28-04 clinical trial from Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and Group 4 (Group 2 + Group 3) determined to have a non-C2 IFN- g Dominant Six Class Immune Signature score.
  • the x-axis depicts months from randomization.
  • the y-axis depicts the probability of being alive. Legend: _ Group 1; - Group 2;
  • Fig. 1 1 is a schematic representing the number of expanded T-cell clones determined by the differential abundance analysis of T-cell receptor b sequences in whole blood from patients receiving trilaciclib or placebo at after induction and prior to starting maintenance versus baseline (prior to induction). Horizontal bars indicate median number of expanded clones in each group.
  • Fig. 12 is a schematic representing the number of expanded T-cell clones determined by the differential abundance analysis of T-cell receptor b sequences in whole blood from responders and non-responders at after induction and prior to starting maintenance versus baseline (prior to induction). Horizontal bars indicate median number of expanded clones in each group.
  • Fig. 13 is a schematic representing the number of newly expanded T-cell clones in responders and non-responders receiving placebo or trilaciclib at after induction and prior to starting maintenance versus baseline (prior to induction). Horizontal bars indicate median number of expanded clones in each group.
  • FIG. 14 is a is a schematic representing the fraction of newly expanded T-cell clones in responders and non-responders receiving placebo or trilaciclib at after induction and prior to starting maintenance versus baseline (prior to induction). Horizontal bars indicate median number of expanded clones in each group.
  • An“effective amount” as used herein means an amount which provides a therapeutic or prophylactic benefit.
  • To“treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e. palliative treatment) or to decrease a cause or effect of the disease or disorder (i.e. disease-modifying treatment).
  • the“host,”“subject,”“patient,” or“individual” to be treated according to the methods described herein is a mammal, including a human.
  • compositions comprising at least one active agent, and at least one other substance, such as a carrier.
  • “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
  • “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • Lists of additional suitable salts may be found, e.g.,
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • ICI immune checkpoint inhibitor
  • ICIs include those targeting immune checkpoint proteins such as programmed cell death- 1 protein (PD-1), PD-1 Ligand- 1 (PD-L1), PD-1 Ligand-2 (PD-L2), CTLA-4, LAG-3, TIM-3, and V-domain Ig suppressor of T-cell activation (VISTA), B7- H3/CD276, indoleamine 2,3 -di oxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEAC AM- 3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and B and T lymphocyte attenuator (BTLA) protein.
  • Immune checkpoint inhibitors are known in the art.
  • the term“CDK4/6-replication independent cancer” refers to a cancer that does not significantly require the activity of CDK4/6 for replication. Cancers of such type are often, but not always, characterized by (e.g., that has cells that exhibit) an increased level of CDK2 activity or by reduced expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s), such as, but not limited to pl07 and pl30.
  • the increased level of CDK2 activity or reduced or deficient expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s) can be increased or reduced, for example, compared to normal cells.
  • the increased level of CDK2 activity can be associated with (e.g., can result from or be observed along with) MYC proto-oncogene amplification or overexpression. In some embodiments, the increased level of CDK2 activity can be associated with overexpression of Cyclin El, Cyclin E2, or Cyclin A.
  • the term“CDK4/6-replication dependent cancer” refers to a cancer that requires the activity of CDK4/6 for replication or proliferation, or which may be growth inhibited through the activity of a selective CDK4/6 inhibitor.
  • Cancers and disorders of such type may be characterized by (e.g., that has cells that exhibit) the presence of a functional Retinoblastoma (Rb) protein. Such cancers and disorders are classified as being Rb-positive.
  • tumor-related or immune-related biomarkers may be used as a predictor of whether an anti-tumor effect can be realized with the addition of a CDK4/6 inhibitor to a chemotherapeutic regime, including an ICD-inducing chemotherapy.
  • predictive biomarkers include the expression of immunosuppressive molecules (such as PD-L1) by tumor cells; the molecular profiling of the tumor microenvironment, which encompasses the expression of inflammatory genes; the assessment of the mutational landscape and neoantigen load; mismatch- repair deficiency and MSI; tumor aneuploidy; immune infiltration; and immunoscore (see generally Galon, T, and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies , Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated by reference herein).
  • SCNA somatic copy-number alteration
  • Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumours with combination immunotherapies describe a large number of strategies in treating tumors in a way to induce improved immune responses, it does not describe the use of a CDK4/6 inhibitor in combination with an ICD-inducing chemotherapy to do so (see Fig. 6).
  • the Galon article highlights the inventive and surprising aspect of the present invention because, despite the comprehensiveness of the article in a prestigious scientific journal, it did not mention or suggest the judicious use or the appropriate selection of a protocol that includes a CDK4/6 inhibitor in the immunogram as part of an effective anticancer therapy that can increase progression free survival or overall survival in a cancer patient. This clinical result is surprising.
  • Additional parameters including tumor foreignness, general immune status, immune cell infiltration, absence of checkpoints, absence of soluble inhibitors, absence of inhibitory tumor metabolism, and tumor sensitivity to immune effectors can be used to determine whether an anti tumor effect resulting in an increased overall survival can be realize with the addition of a CDK4/6 inhibitor to their chemotherapeutic regime.
  • the evaluation of these factors can be achieved by a combination of tumor genomics, immunoscore assay, immunohistochemistry, standard blood assays and immune gene signature, both pre-therapy and post-therapy (see Blank et ah, The “cancer immunogram Science 352, 658-660 (2016), incorporated herein by reference).
  • tumors can be classified based on certain immunogenic characteristics. Importantly, it has been observed that a tumor may progress over time through the various classifications. Also, it has been observed that, in certain instances, a type of tumor may have different immunogenic characteristics in different individuals.
  • hot immune tumors are those that have (i) a high degree of T-cell and cytotoxic T cell infiltration, i.e., a high immunoscore; and (ii) ability for checkpoint activation (programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte- associated antigen 4 (CTLA4), T-cell immunoglobulin mucin receptor 3 (TIM3) and lymphocyte activation gene 3 (LAG3)) or otherwise impaired T-cell functions (for example, extracellular potassium- driven T-cell suppression).
  • PD-1 programmed cell death protein 1
  • CTLA4 cytotoxic T lymphocyte- associated antigen 4
  • TIM3 T-cell immunoglobulin mucin receptor 3
  • LAG3 lymphocyte activation gene 3
  • TILs tumor-infiltrating lymphocytes
  • PD-L1 anti-programmed death-ligand 1
  • hot tumors characteristically display possible genomic instability and the presence of a pre-existing antitumor immune response. See, e.g., in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies , Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety.
  • Tumors often observed to have characteristics of hot immune tumors include, but are not limited to, bladder cancers, renal cell carcinoma, liver cancer (hepatocellular carcinoma), non small cell lung cancer, colon adenocarcinoma, breast invasive carcinoma, cholangiocarcinoma, esophageal carcinoma, Merkel cell carcinoma, HPV+ head and neck squamous cell carcinomas, advanced-stage melanoma, skin cutaneous melanoma, endometrial cancer, gastric cancer and cervical cancer; Hodgkin lymphoma, diffuse large B-cell lymphoma; and tumors with microsatellite instability (MSI).
  • An exemplified resected tumor having the characteristics of a hot immune tumor is illustrated in Fig. 7A.
  • Altered-immunosuppressed tumors are categorized by (i) poor, albeit not absent, T-cell and cytotoxic T-cell infiltration (intermediate immunoscore), (ii) presence of soluble inhibitory mediators (transforming growth factor- b (TGFP), interleukin 10 (IL-10) and vascular endothelial growth factor (VEGF)), (iii) the presence of immune suppressive cells (myeloid- derived suppressor cells and regulatory T-cells), and (iv) presence of T-cell checkpoints (PD-1, CTLA4, TIM3 and LAG3). Altered-immunosuppressed tumor sites display a low degree of immune infiltration (FIG.
  • altered-excluded immune tumors are (i) no T-cell infiltration inside the tumor bed; accumulation of T-cells at tumor borders (invasive margin) (intermediate immunoscore), (ii) activation of oncogenic pathways, (iii) epigenetic regulation and reprogramming of the tumor microenvironment, (iii) aberrant tumor vasculature and/or stroma, and (iv) hypoxia.
  • T-cells are found at the edge of tumor sites (invasive margin) without being able to infiltrate them.
  • This‘excluded’ phenotype reflects the intrinsic ability of the host immune system to effectively mount a T-cell-mediated immune response and the ability of the tumor to escape such response by physically hindering T-cell infiltration (FIG. 7A). See, e.g., in Galon, J., and Bruni, D., Approaches to treat immune hot, altered and cold tumors with combination immunotherapies , Nature Reviews Drug Discovery (18), March 2019, 197-218, incorporated herein in its entirety. An exemplified resected tumor having the characteristics of an altered-excluded immune tumor is illustrated in Fig. 7A.
  • the characteristics of a cold tumor are: (i) absence of T-cells within the tumor and at the tumor edges (low immunoscore), and (ii) failed T-cell priming (low tumor mutational burden, poor antigen presentation and intrinsic insensitivity to T-cell killing).
  • Cold tumors can also show a low expression of PD-L1.
  • cold tumors Apart from being poorly infiltrated, cold tumors have also been described to be immunologically unaware (scarcely expressing PD-L1) and characterized by high proliferation with low mutational burden (low expression of neoantigens) and low expression of antigen presentation machinery markers such as major histocompatibility complex class I (MHC I).
  • MHC I major histocompatibility complex class I
  • Fig. 7A An exemplified resected tumor having the characteristics of cold immune tumor is illustrated in Fig. 7A.
  • Nonimmunogenic, or“cold” tumors have not yet been infiltrated with T cells, a sign that the immune response is not working in these tumors.
  • the lack of T cells makes it difficult to provoke an immune response with immunotherapy drugs.
  • the microenvironment surrounding cold tumors contains myeloid-derived suppressor cells (MDSC) and T regulatory cells (Tregs), which are known to dampen the immune response and inhibit T cells trying to move into the tumor. Additional features of cold tumors include lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of CD8+ homing into the tumor bed.
  • breast cancers ovarian cancer, prostate cancer, pancreatic cancer, neuroblastoma, small-cell lung cancer, and glioblastomas are typically cold tumors.
  • the determination of the immunogenic classification of a tumor can be carried out on resected tumors (primary or metastatic) (see e.g., Fig. 7A).
  • Less invasive diagnostic procedures such as immuno-positron-emission tomography (PET) imaging detecting intratumoral CD8+ T- cells can also be used.
  • PET immuno-positron-emission tomography
  • CIBERSORT which infers the relative fractions of immune subsets in the total leukocyte population
  • xCell which predicts the abundance of immune cells in the overall TME
  • TIMER which generates enrichment scores on the basis of proportions among 64 immune and stromal cell types
  • integrated immunogenomics methods using a CIBERSORT- based approach, which, of note, identified six immune subtypes of cancer
  • can be used to estimate the abundance of intra-tumoral immune infiltrates by using deconvolution of bulk gene expression data see Newman et al., Robust enumeration of cell subsets from tissue expression profiles , Nat.
  • Immunoscore is a digital pathology, IHC -based immune assay measuring the densities of CD3+ and CD8+ T cells at different tumor locations.
  • the Immunoscore scoring has been defined in a large international SITC-led retrospective validation study conducted on more than 2500 St I- III colon cancer patients (see Pages et al, International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study , The Lancet Volume 391, ISSUE 10135, P2128-2139, May 26, 2018, incorporated herein by reference).
  • Commercial Immunoscore assays are available through, for example, HalioDx, Inc. (Richmond, Va).
  • FFPE paraffin-embedded
  • Image analysis is performed via a dedicated software (Immunoscore Analyzer, HalioDx): automatic detection of the tissue histologic structure is followed by an operator-guided definition of the tumor, healthy tissue (submucosa, muscularis intestinal, serosa), and the epithelium (mucosa). The operator also excludes all areas of necrosis, abscess, and artifacts (bubbles folds, torn areas, background) to avoid false positives.
  • the IM spanning 360 pm into the healthy tissue and 360 pm into the tumor, is calculated automatically by the software. In the presence of multiple FFPE blocks, the one to select for the Immunoscore evaluation is the one containing the IM.
  • An additional measure for predicting the anti-tumor effect of CDK4/6 inhibitor therapy is determining the tumor’s IFN-g Signature Score and/or Expanded Immune Signature Score as described in Ayers et al. Ayers M, et al.“ IFN-y RelatedMKNA Profile Predicts Clinical Response to PD-1 Blockade Journal of Clinical Investigation, vol. 127, no. 8, 2017, pp. 2930-2940., doi: 10.1172/jci91190 (incorporated herein by reference in its entirety), who outline a thorough, iterative approach to building a gene expression signature predictive of response to immune checkpoint inhibitors (e.g., pembrolizumab).
  • immune checkpoint inhibitors e.g., pembrolizumab
  • the IFN-g Signature analysis consists of determining the expression profile of six genes: IDOl, CXCL10, CXCL9, HLA-DRA; STAT1, and IFN-g.
  • the Expanded Immune Signature analysis consists of determining the expression profile of 18 genes: CCL5, CD27, CD274, CD276, CD8A, CMKLR1, CXCL9, CXCR6, HLA-DRB 1, HLA-DQA1, HLA-E, IDOl, LAG3, NKG7, PDCD1LG2, PSMB10, STAT1, and TIGIT.
  • Ayers et al. performed sequencing quantitation using a 680 gene panel on the Nanostring platform.
  • To compute a sample’s score for either multi-gene signature IFN-g Signature or Expanded Immune Signature
  • quantile normalization is performed prior to a loglO transformation and subsequent averaging across the gene-set.
  • Calculation of the area under the ROC curve was used as a measure of discriminatory ability for the signature scores.
  • the Youden index a summary measure of the ROC curve (see Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32— 35, incorporated herein by reference), was used as an agnostic method for choosing an“optimal” cutoff , that is“high”/”low” on the signature scores to illustrate potential clinical usefulness.
  • a“high” IFN-g Signature or Expanded Immune Signature can be determined based on comparison to scores of known immunogenic samples.
  • a“high” IFN-g Signature or Expanded Immune Signature score is one that is scored greater than at least 2.25, 2.5, or 2.75.
  • a“high” IFN-g Signature or Expanded Immune Signature score is one that is scored greater than at least 2.5.
  • the assessment provides a tumor type-independent applicability of a T-cell-inflamed gene expression profile that captures the biology of a T-cell inflamed microenvironment and as shown in the example below, TNBC patients having high IFN-g Signature Scores and/or Enhanced Immune Signature Scores who are administered a CDK4/6 inhibitor show statistically significant overall survival improvements compared to those who do not receive a CDK4/6 inhibitor.
  • TNBC patients with tumors in the C2“IFN-g Dominant” category administered a CDK4/6 inhibitor show statistically significant overall survival improvements compared to those that are C2“IFN-g Dominant” that do not receive a CDK4/6 inhibitor during treatment.
  • PD-L1 programmed death- 1 ligand
  • PD-1 is a transmembrane protein that down-regulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1.
  • PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of chronic stimulation such as in chronic infection or cancer (Blank, C and Mackensen, A, Contribution of the PD-L1/PD- 1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745).
  • B7.1 is a molecule expressed on antigen presenting cells and activated T cells.
  • PD-L1 binding to B7.1 on T cells and antigen presenting cells can mediate down- regulation of immune responses, including inhibition of T-cell activation and cytokine production (see Butte MJ, Keir ME, Phamduy TB, et al.
  • Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1): 111-122).
  • PD-L1 expression has been observed in immune cells and tumor cells.
  • interruption of the PD- Ll/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific T cell immunity suppressed by the expression of PD-L1 in the tumor microenvironment.
  • the upregulation of PD-L1 may allow cancers to evade the host immune system.
  • PD-L1 expression can be determined by methods known in the art.
  • PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, the FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol-Meyers Squibb as a companion test for treatment with pembrolizumab.
  • IHC in vitro diagnostic immunohistochemistry
  • This is qualitative assay using Monoclonal Mouse Anti-PD-Ll, Clone 22C3 PD-L1 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human non-small cell lung cancer tissue.
  • Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining. Staining can show PD-L1 expression from 1% to 100%.
  • TPS tumor proportion score
  • PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab.
  • IHC in vitro diagnostic immunohistochemistry
  • This qualitative assay uses the Monoclonal rabbit anti-PD-Ll, Clone 28-8 and EnVision FLEX visualization system on Autostainer Lin 48 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human non-small cell lung cancer tissue.
  • FFPE paraffin-embedded
  • PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca) that utilizes monoclonal rabbit anti- PD-Ll, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-Ll clone SP142. Determination of PD- L1 status is indication-specific, and evaluation is based on either the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity or the percentage of PD-L1 expressing tumor cells (% TC) of any intensity.
  • % IC proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells
  • % TC percentage of PD-L1 expressing tumor cells
  • PD-L1 expression in > 5% IC determined by, for example, the Ventana PD-L1 (SP142) Assay in urothelial carcinoma tissue, whereas a PD-L1 positive status in TNBC is considered > 1% IC and NSCLC is considered > 50% TC or > 10% IC.
  • SP142 Ventana PD-L1
  • Short-acting CDK4/6 inhibitors for use in the present invention include Compound I, Compound II, Compound III, Compound IV, and Compound V, or pharmaceutically acceptable salts thereof.
  • Compound I known as trilaciclib (2'-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)- 7',8'-dihydro-6'H-spiro(cyclohexane-l,9'-pyrazino(r,2': l,5)pyrrolo(2,3-d)pyrimidin)-6'-one) is a highly selective CDK4/6 inhibitor having the structure:
  • trilaciclib or its pharmaceutically acceptable salt, composition, isotopic analog, or prodrug thereof is administered in a suitable carrier in a chemotherapeutic regime that includes an immune-response inducing chemotherapy such as an ICD-inducing chemotherapeutic.
  • a chemotherapeutic regime that includes an immune-response inducing chemotherapy such as an ICD-inducing chemotherapeutic.
  • Trilaciclib is described in U.S. Patent No. 8,598, 186, incorporated herein by reference in its entirety.
  • Trilaciclib can be synthesized as described in WO 2019/0135820, incorporated herein by reference in its entirety.
  • Trilaciclib in one embodiment, may be administered parenterally, for example, intravenously, to a patient prior to administration of an immune-response inducing chemotherapy such as an ICD-inducing chemotherapy.
  • trilaciclib is administered up to about 24 hours or less, or up to about 20, 15, 10, 5, or 4 hours or less for example about 30-60 minutes or less, prior to administration of the chemotherapy.
  • trilaciclib is administered approximately about 22 to 26 hours before administration of the chemotherapy, and again about 4 hours or less, for example about 30-60 minutes or less, prior to administration of the chemotherapy.
  • the dose of trilaciclib administered is between about 180 and about 280 mg/m 2 .
  • the dose is up to about 100, 125, 150, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or 280 mg/m 2 or any dose in between these numbers as determined desirable by the healthcare practitioner.
  • the dose is about 240 mg/m 2 .
  • Trilaciclib can be administered in any manner that achieves the desired outcome, including systemically, parenterally, intravenously, intramuscularly, subcutaneously, or intradermally.
  • trilaciclib may be provided, in one embodiment, for example, as a 300 mg/vial as a sterile, lyophilized, yellow cake providing 300 mg of trilaciclib (equivalent to 349 mg of trilaciclib dihydrochloride).
  • the product for example, may be supplied in single-use 20-mL clear glass vials and does not contain a preservative.
  • trilaciclib for injection 300 mg/vial may be reconstituted with 19.5 ml of 0.9% sodium chloride injection or 5% dextrose injection. This reconstituted solution has a trilaciclib concentration of 15 mg/mL and would typically be subsequently diluted prior to intravenous administration.
  • Lerociclib (2'-((5-(4- isopropylpiperazin-l-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-l,9'- pyrazino[T,2': l,5]pyrrolo[2,3-d]pyrimidin]-6'-one) has the chemical structure:
  • Lerociclib can be administered in any manner that achieves the desired effect, including systemically, parenterally, orally, intravenously, intramuscularly, subcutaneously, or intradermally.
  • Lerociclib can be prepared as previously described in WO 2014/144325, incorporated herein by reference.
  • lerociclib is administered using the same suggested amounts and methods as above for trilaciclib.
  • the CDK4/6 inhibitor having the structure:
  • Compound II is administered instead of trilaciclib.
  • this compound is administered using the same suggested amounts and methods as above for trilaciclib.
  • the CDK4/6 inhibitor having the structure:
  • this compound is administered using the same suggested amounts and methods as above for trilaciclib.
  • the CDK4/6 inhibitor having the structure:
  • Ci straight, branched or cyclic Ci to Cs alkyl group, including methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, and cyclopentyl; and
  • Y is NR1R2 wherein Ri and R2 are independently X, or wherein Ri and R2 are alkyl groups that together form a bridge that includes one or two heteroatoms (N, O, or S);
  • two X groups can together form an alkyl bridge or a bridge that includes one or two heteroatoms (N, S, or O) to form a spiro compound, or its pharmaceutically acceptable salt, is administered instead of trilaciclib.
  • a compound selected from this formula is administered using the same suggested amounts and methods as above for trilaciclib.
  • a CDK4/6 inhibitor other than those specifically described above can be used in the present invention.
  • Non-limiting examples include palbociclib, abemaciclib, and ribociclib.
  • the CDK4/6 inhibitor may be formulated as any pharmaceutically useful form, e.g., as a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a subcutaneous injection, a dry powder, buccal, or sublingual formulation, parenteral formulation, or other suitable administration formulation.
  • a pharmaceutically useful form e.g., as a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a subcutaneous injection, a dry powder, buccal, or sublingual formulation, parenteral formulation, or other suitable administration formulation.
  • Standard cancer chemotherapy can promote tumor immunity in two major ways: (i) inducing immunogenic cell death as part of its intended therapeutic effect; and (ii) disrupting strategies that tumors use to evade the immune response.
  • a large body of data demonstrates that some chemotherapy drugs at their standard dose and schedule mediate their antitumor effect, at least in part, by inducing immunogenic cell death (see, e.g., Emens et ah, Chemotherapy: friend of foe to cancer vaccines? Curr Opin Mol Ther 2001;3:77-84; Vanmeerbeek et ah, Trial Watch: Chemotherapy-Induced Immunogenic Cell Death in Immuni-Oncology . Oncoimmunology Vol. 9, No. 1 2020:el703449, both incorporated by reference herein).
  • Immunogenic cell death is a type of cell death characterized by, for example, cell surface translocation of calreticulin (CRT), extracellular release of ATP and high mobility group box 1 (HMBG1), and stimulation of type I interferon (IFN) responses.
  • CRT cell surface translocation of calreticulin
  • HMBG1 high mobility group box 1
  • IFN type I interferon
  • ICD in cancer cells may prime an anticancer immune response.
  • a variety of chemotherapeutic agents can induce ICD, as indicated by the alterations in tumor-infiltrating lymphocytes (TIL) abundance and composition.
  • tumor cells In response to ICD-inducing chemotherapeutics, tumor cells expose CRT on cell surface prior to death, and release damage-associated molecular pattern (DAMP) molecules such as ATP during apoptosis or HMGB 1 upon secondary necrosis. These DAMPs stimulate the recruitment of dendritic cells (DCs) into the tumor bed, the uptake and processing of tumor antigens, and the optimal antigen presentation to T cells. Cross-priming of CD8+ T-cells is triggered by mature DCs and gd T-cells in an IL-Ib and IL-17 dependent manner. Primed CTLs then elicit a direct cytotoxic response to kill remaining tumor cells through the generation of IFN-g, perforin- 1 and granzyme B.
  • DAMP damage-associated molecular pattern
  • ICD-inducing chemotherapies for use in the present invention include alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitroxantrone, gemcitabine, and 5-fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes, such as paclitaxel, cabazitaxel, and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan, and etoposide; platinum compounds such as carboplatin and cisplatin; anti -microtubule vinca alkaloid agents such as vinblastine, vincristine, vinorelbine, and vindesine
  • ICD-inducing chemotherapies include bortezomib, an inhibitor of the 26S proteasome subunit, mechlorethamine, diaziquone, mitomycin C, fludarabine and cytosine arabinoside.
  • the ICD-inducing chemotherapy is selected from idarubicin, epirubicin, doxorubicin, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, and combinations thereof.
  • the chemotherapeutic administered is capable of inducing an immune-response may modulate tumor immunity by mechanisms distinct from immunogenic cell death.
  • Various chemotherapy drugs can modulate the activity of distinct immune cell subsets or the immune phenotype of tumor cells through enhancing antigen presentation, enhancing expression of costimulatory molecules including B7.1 (CD80) and B7.2 (CD86), downregulating checkpoint molecules such as programmed death-ligand 1 (PD-L1), or promoting tumor cell death through the fas, perforin, or Granzyme B pathways.
  • costimulatory molecules including B7.1 (CD80) and B7.2 (CD86)
  • PD-L1 programmed death-ligand 1
  • Chemotherapies that modulate tumor immunity may do so by: abrogating myeloid-derived suppressor cell (MDSC) activity, for example gemcitabine, 5-fluoruracil, cisplatin, and doxorubicin; abrogating Treg activity, for example cyclophosphamide, 5- fluorouracil; paclitaxel, cisplatin, and fludarabine; enhancement of T-cell cross priming, for example gemcitabine and anthracyclines such as doxorubicin, daunorubicin, epirubicin, valrubicin and idarubicin.; augmenting dendritic cell activation, for example anthracyclines, taxanes, cyclophosphamide, vinca alkaloids, methotrexate, and mitomycin C; promoting anti-tumor CD4+ T-cell phenotype, for example cyclophosphamide and paclitaxel; and promoting tumor cell recognition and lysis, for example
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of an alkylating agent such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, or oxaliplatin; an antimetabolite such as methotrexate, mitroxantrone, gemcitabine, or 5-fluorouracil (5-FU); a cytotoxic antibiotic such as bleomycin or an anthracycline such as doxorubicin, daunorubicin, epirubicin, idarubicin,
  • the administration of the CDK4/6 inhibitor in combination with the chemotherapy does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor.
  • the patient has an altered-immunosuppressed immune tumor.
  • the patient has an altered- excluded immune tumor.
  • the patient has a cold tumor.
  • the patient has a tumor that is classified as a C2“IFN-g Dominant” class cancer.
  • the patient has a tumor that is classified as a high“IFN-g Signature” or a high “Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive.
  • the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of cyclophosphamide.
  • the administration of the short acting CDK4/6 inhibitor in combination with cyclophosphamide does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2“IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of trabectedin.
  • the administration of the short acting CDK4/6 inhibitor in combination with trabectedin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of temozolomide.
  • the administration of the short acting CDK4/6 inhibitor in combination with temozolomide does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of melphalan.
  • the administration of the short acting CDK4/6 inhibitor in combination with melphalan does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of dacarbazine.
  • the administration of the short acting CDK4/6 inhibitor in combination with dacarbazine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein.
  • the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of oxaliplatin.
  • the administration of the short acting CDK4/6 inhibitor in combination with oxaliplatin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor.
  • the patient has an altered-immunosuppressed immune tumor.
  • the patient has an altered-excluded immune tumor.
  • the patient has a cold tumor.
  • the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer.
  • the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive.
  • the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of methotrexate.
  • the administration of the short acting CDK4/6 inhibitor in combination with methotrexate does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of 5-fluorouracil (5-FU).
  • the administration of the short acting CDK4/6 inhibitor in combination with 5-FU does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of gemcitabine.
  • the administration of the short acting CDK4/6 inhibitor in combination with gemcitabine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor.
  • the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of mitoxantrone.
  • the administration of the short acting CDK4/6 inhibitor in combination with mitoxantrone does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of doxorubicin.
  • the administration of the short acting CDK4/6 inhibitor in combination with doxorubicin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of daunorubicin.
  • the administration of the short acting CDK4/6 inhibitor in combination with daunorubicin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of idarubicin.
  • the administration of the short acting CDK4/6 inhibitor in combination with idarubicin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of valrubicin.
  • the administration of the short acting CDK4/6 inhibitor in combination with valrubicin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of epirubicin.
  • the administration of the short acting CDK4/6 inhibitor in combination with epirubicin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of bleomycin.
  • the administration of the short acting CDK4/6 inhibitor in combination with bleomycin does not include administering an immune checkpoint inhibitor.
  • the patient has a hot immune tumor.
  • the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered- excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2“IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high “Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of bortezomib.
  • the administration of the short acting CDK4/6 inhibitor in combination with bortezomib does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein.
  • the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of paclitaxel.
  • the administration of the short acting CDK4/6 inhibitor in combination with paclitaxel does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of docetaxel.
  • the administration of the short acting CDK4/6 inhibitor in combination with docetaxel does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of cabazitaxel.
  • the administration of the short acting CDK4/6 inhibitor in combination with cabazitaxel does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of topotecan.
  • the administration of the short acting CDK4/6 inhibitor in combination with topotecan does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of etoposide.
  • the administration of the short acting CDK4/6 inhibitor in combination with etoposide does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of irinotecan.
  • the administration of the short acting CDK4/6 inhibitor in combination with irinotecan does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of cisplatin.
  • the administration of the short acting CDK4/6 inhibitor in combination with cisplatin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of carboplatin.
  • the administration of the short acting CDK4/6 inhibitor in combination with carboplatin does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of vinblastine.
  • the administration of the short acting CDK4/6 inhibitor in combination with vinblastine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor.
  • the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of vincristine.
  • the administration of the short acting CDK4/6 inhibitor in combination with vincristine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of vinorelbine.
  • the administration of the short acting CDK4/6 inhibitor in combination with vinorelbine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of vindesine.
  • the administration of the short acting CDK4/6 inhibitor in combination with vindesine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor.
  • the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein.
  • the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of diaziquone.
  • the administration of the short acting CDK4/6 inhibitor in combination with diaziquone does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic. In some embodiments, the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of mechlorethamine.
  • the administration of the short acting CDK4/6 inhibitor in combination with mechlorethamine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of mitomycin C.
  • the administration of the short acting CDK4/6 inhibitor in combination with mitomycin C does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of fludarabine.
  • the administration of the short acting CDK4/6 inhibitor in combination with fludarabine does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2 “IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population is provided comprising, determining if the cancer has a surrounding microenvironment that is favorable to immune modulation, is immunogenically susceptible to CDK4/6 inhibitor treatment, or is immunogenic, and if so, administering to the patient an effective amount of a CDK4/6 inhibitor in combination with an effective amount of cytosine arabinoside.
  • the administration of the short acting CDK4/6 inhibitor in combination with cytosine arobinoside does not include administering an immune checkpoint inhibitor.
  • the patient has a tumor classified as immunogenic.
  • the patient has a hot immune tumor. In some embodiments, the patient has an altered-immunosuppressed immune tumor. In some embodiments, the patient has an altered-excluded immune tumor. In some embodiments, the patient has a cold tumor. In some embodiments, the patient has a tumor that is classified as a C2“IFN-g Dominant” class cancer. In some embodiments, the patient has a tumor that is classified as a high“IFN-g Signature” or a high“Expanded Immune Signature.” In some embodiments, the patient has a tumor that is PD-L1 positive. In some embodiments, the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt therein. In some embodiments, the CDK4/6 inhibitor administered is Compound III, or a pharmaceutically acceptable salt therein.
  • the patient to be treated has been determined to have a cancer having a surrounding microenvironment that is favorable to immune modulation, is immunogenic, or is immunogenically susceptible to CDK4/6 inhibitor treatment. Accordingly, provided the cancer fits into the category as described herein, the patient may be suitable for the described treatments.
  • the cancer to be treated is selected from the group consisting of breast cancer, including but not limited to estrogen receptor (ER)-positive breast cancer and triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, microsatellite instability- high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, endometrial cancer, cholangiocarcinoma, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, skin cutaneous melanoma and melanoma.
  • cHL central lymphoma
  • PBMCL
  • a method for selecting a patient or patient population for triple negative breast cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population comprising administering to the patient gemcitabine and carboplatin and administering a CDK 4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to the administration of gemcitabine and carboplatin, and wherein the cancer is, prior to initiation of treatment, determined to be immunogenic, immunogenically susceptible to CDK4/6 inhibitor treatment, or have a surrounding microenvironment that is favorable to immune modulation.
  • a patient or patient population for triple negative breast cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population comprising administering to the patient gemcitabine and carboplatin on Days 1 and 8 of 21 -day cycles; administering a CDK 4/6 inhibitor selected from Compound I, Compound II, Compound III, Compound IV, or a pharmaceutically acceptable salt thereof, wherein the CDK4/6 inhibitor is administered prior to the administration of gemcitabine and carboplatin, and wherein the triple negative cancer is, prior to initiation of treatment, determined to be immunogenic, immunogenically susceptible to CDK4/6 inhibitor treatment, or have a surrounding microenvironment that is favorable to immune modulation.
  • Administration Protocols are examples of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population comprising administering to the patient gemcitabine and carboplatin on Days 1 and 8 of 21 -day cycles; administering a CDK 4/6 inhibitor
  • the methods described herein provide for the administration of a CDK4/6 inhibitor with a chemotherapy capable of inducing an immune-mediated response in a cancer, for example an ICD- inducing chemotherapy for extending the overall survival or progression free survival of a patient with cancer, such methods including determining if the patient has a cancer that can be classified as immunogenic, or has a surrounding microenvironment that is favorable to immune modulation, or is susceptible to, or the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment, and if so, administer to the patient a chemotherapeutic agent capable of inducing an immune- mediated response in combination with a CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is administered prior to or concomitantly with the administration of the chemotherapeutic agent.
  • the selective CDK4/6 inhibitor is administered to the subject less than about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 8 hours, about 4 hours, about 2.5 hours, about 2 hours, about 1 hour, about 1 ⁇ 2 hour or less prior to treatment with the chemotherapeutic agent.
  • the selective CDK4/6 inhibitor is administered about 1 ⁇ 2 hour prior to administration of the chemotherapeutic agent.
  • the selective CDK4/6 inhibitor is administered to the subject prior to treatment with the chemotherapeutic agent such that the CDK4/6 inhibitor reaches peak serum levels before or during treatment with the chemotherapeutic agent, allowing for the inhibition of proliferation of immune effector cells, thus protecting them from the harmful effects of chemotherapy.
  • the CDK4/6 inhibitor is administered concomitantly, or closely thereto, with the chemotherapeutic agent exposure.
  • the selective CDK4/6 inhibitor is Compound I, or a pharmaceutically acceptable salt thereof.
  • the selective CDK4/6 inhibitor is Compound III, or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is administered to the subject less than about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 8 hours, about 4 hours, about 2.5 hours, about 2 hours, about 1 hour, about 1 ⁇ 2 hour or less prior to treatment with the chemotherapeutic agent.
  • the selective CDK4/6 inhibitor is administered about 1 ⁇ 2 hour prior to administration of the chemotherapeutic agent.
  • the CDK4/6 inhibitor is administered to the subject prior to treatment with the chemotherapeutic agent such that the CDK4/6 inhibitor reaches peak serum levels before or during treatment with the chemotherapeutic agent, allowing for the inhibition of proliferation of immune effector cells, thus protecting them from the harmful effects of chemotherapy.
  • the CDK4/6 inhibitor is administered concomitantly, or closely thereto, with the chemotherapeutic agent exposure.
  • the CDK4/6 inhibitor described herein can be administered following exposure to the chemotherapeutic agent if desired to mitigate immune effector cell damage associated with chemotherapeutic agent exposure.
  • the CDK4/6 inhibitor is administered to the subject twice before administration of the chemotherapy.
  • the CDK4/6 inhibitor is administered between about 18 and 28 hours before the administration of the chemotherapy, and then once again at less than about 4 hours, about 2.5 hours, about 2 hours, about 1 hour, about 1 ⁇ 2 hour or less prior to treatment with the chemotherapeutic agent.
  • the selective CDK4/6 inhibitor is administered between about 22 and 26 hours prior to administration of the chemotherapeutic agent and again about 1 ⁇ 2 hour or less prior to administration of the chemotherapeutic agent.
  • the CDK4/6-inhibitor is administered prior to or concomitantly with the administration of a chemotherapeutic agent, wherein the chemotherapeutic agent is administered: for example, on day 1-3 every 21 days; on days 1-3 every 28 days; on day 1 every 3 weeks; on day 1, day 8, and day 15 every 28 days, on day 1 and day 8 every 28 days; on days 1 and day 8 every 21 days; on days 1-5 every 21 days; 1 day a week for 6-8 weeks; on days 1, 22, and 43; days 1 and 2 weekly; days 1-4 and 22-25; days 1-4; days 22-25, and days 43-46; and similar type chemotherapeutic regimens.
  • the CDK4/6 inhibitor is administered prior to or concomitantly with at least one administration of the chemotherapeutic agent during a chemotherapeutic treatment regimen. In some embodiments, the CDK4/6 is administered prior to or concomitantly with one or more administrations of the chemotherapeutic agent during a chemotherapeutic treatment regimen. In one embodiment, the CDK4/6 inhibitor is administered prior to or concomitantly with each administration of the chemotherapeutic agent during a chemotherapeutic treatment regimen.
  • the CDK4/6 inhibitor is administered prior to or concomitantly with each administration of a chemotherapeutic agent for example during a standard chemotherapeutic protocol such as, for example, a 21 -day cycle. Following cessation of the standard chemotherapeutic protocol, the CDK4/6 inhibitor is further administered alone in a maintenance dose. In some embodiments, the CDK4/6 inhibitor is further administered once a week for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 26, 52, 104 weeks, or longer. In some embodiments, the CDK 4/6 inhibitor is administered once every 21 days following the cessation of the chemotherapeutic protocol. In one embodiment, the selective CDK4/6 inhibitor is a fast-acting, short half-life CDK4/6 inhibitor.
  • the CDK4/6 inhibitor is administered with a chemotherapy agent in a maintenance therapy treatment regimen following cessation of the standard chemotherapeutic protocol.
  • Maintenance therapy can comprise either continuation of an agent given as part of the first-line or previous regimen (continuation maintenance) or treatment with a new agent (switch maintenance).
  • the CDK4/6 inhibitor is further administered in a maintenance-type therapeutic regimen, wherein the CDK4/6 inhibitor is administered in combination with a reduced maintenance dose of chemotherapy at a regular dosing interval for example but not limited to, once a week, once every two weeks, once every three weeks, once a month, once every six weeks, once every two months, once every three months, or once every six months following the completion of the initial chemotherapy treatment.
  • the CDK4/6 inhibitor is administered with the same agent used in the previous phase of chemotherapy treatment.
  • the CDK4/6 inhibitor is administered with a different chemotherapy agent than was used in the previous phase of chemotherapy treatment.
  • the patient is not administered a check point inhibitor.
  • a method for selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient comprising:
  • R is C(H)X, NX, C(H)Y, or C(X) 2,
  • Ci straight, branched or cyclic Ci to Cs alkyl group, including methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, cyclobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, and cyclopentyl; and
  • Y is NR1R2 wherein Ri and R2 are independently X, or wherein Ri and R2 are alkyl groups that together form a bridge that includes one or two heteroatoms (N, O, or S);
  • two X groups can together form an alkyl bridge or a bridge that includes one or two heteroatoms (N, S, or O) to form a spiro compound, or a pharmaceutically acceptable salt thereof; wherein the CDK4/6 inhibitor is administered prior to the administration of the chemotherapy or optionally prior to and concurrently with chemotherapy; and, wherein the increase in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone.
  • the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer is an IFN-g Dominant class cancer, has a cancer microenvironment with a high IFN-g Signature, or has a high Expanded Immune Signature, PD-L1 positive, or combination thereof.
  • the chemotherapy is chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5- fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations thereof.
  • the chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin,
  • a method of selecting a patient or patient population for cancer therapy that includes the administration of a CDK 4/6 inhibitor with chemotherapy in a manner that increases the progression free survival or overall survival of the patient or patient population comprising: (i) determining whether the cancer is immunogenic; (ii) determining whether the patient can be administered an ICD-inducing chemotherapy based on the cancer;
  • ICD-inducing chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5- fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations of thereof.
  • the ICD-inducing chemotherapy is selected from the group consisting of cyclophos
  • CDK4/6 inhibitor is administered prior to the administration of the chemotherapy or optionally prior to and concurrently with chemotherapy; wherein the increase in overall survival or progression free survival is in comparison to the overall survival or progression free survival based on administration of the chemotherapy alone.
  • embodiment 36 wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I and class II antigens available to initiate an effective immune response.
  • ICD-inducing chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5-fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations of thereof.
  • the ICD-inducing chemotherapy is selected from the group consisting of cyclophos
  • any of embodiments 36-51 wherein the cancer is selected from the group consisting of triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, microsatellite instability- high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, and melanoma. 53. The method of any of embodiments 36-52, wherein the patient is not administered an immune checkpoint inhibitor at the time of the administration of the CDK4/6 inhibitor.
  • embodiment 54 wherein the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment if the cancer has a surrounding microenvironment that is favorable to immune modulation as assessed according to FIG 6.
  • embodiment 54 wherein the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment if the cancer has a surrounding microenvironment that is favorable to immune modulation as assessed according to the Galon immunoscore system.
  • embodiment 54 wherein the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment if the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I antigens available to initiate an effective immune response.
  • embodiment 54 wherein the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment if the cancer microenvironment has a sufficiently high level of major histocompatibility complex class II antigens available to initiate an effective immune response.
  • embodiment 54 wherein the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment if the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I and class II antigens available to initiate an effective immune response.
  • embodiment 54 wherein the patient has a cancer microenvironment that is a C2 IFN-g Dominant class cancer, has a cancer microenvironment with a high IFN-g Signature or a high Expanded Immune Signature, has a cancer that is PD-L1 positive.
  • any of embodiments 54-69, wherein the ICD-inducing chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5-fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations of thereof.
  • the ICD-inducing chemotherapy is selected
  • any of embodiments 54-70 wherein the cancer is selected from the group consisting of triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, microsatellite instability- high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, and melanoma.
  • cHL codgkin lymphoma
  • PBMCL primary mediastinal B-cell lymphoma
  • urothelial carcinoma microsatellite instability- high (MSI-H) solid tumors
  • embodiment 74 wherein the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises comparing a cancer tissue sample to those characterized in FIG 7.
  • embodiment 74 wherein the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing the cancer according to FIG 6.
  • embodiment 74 wherein the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I antigens available to initiate an effective immune response.
  • invention 74 wherein the determination of cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class II antigens available to initiate an effective immune response.
  • embodiment 74 wherein the determination of whether the cancer is immunogenically susceptible to CDK 4/6 inhibitor comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I and class II antigens available to initiate an effective immune response.
  • embodiment 74 wherein the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing whether the cancer microenvironment has a sufficiently high degree of T cell and cytotoxic T cell infiltration.
  • embodiment 74 wherein the determination of whether the cancer is immunogenically susceptible to CDK4/6 inhibitor treatment comprises assessing whether the cancer has genomic instability and the microenvironment has presence of a pre-existing antitumor immune response.
  • any of embodiments 74-90, wherein the ICD-inducing chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5-fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations of thereof.
  • the ICD-inducing chemotherapy is
  • any of embodiments 74-90, wherein the chemotherapy is an immunogenic cell death (ICD)-inducing chemotherapy.
  • the cancer is selected from the group consisting of triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, microsatellite instability- high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, and melanoma.
  • ICD immunogenic cell death
  • CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with the administration of the chemotherapy, and wherein the improvement in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone.
  • embodiment 97 wherein the determination of whether the cancer is IFN-g dominant is based on a cancer microenvironment having high M1/M2 polarization, strong CD8+ T-cell staining, and a high T-cell receptor diversity.
  • embodiment 97 wherein the determination of whether the cancer is IFN-g dominant is based on the Thorsson et al. Six Class Immune Signature score classification.
  • CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with the administration of the chemotherapy, and wherein the improvement in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone.
  • embodiment 100 wherein the determination of whether the cancer has a high IFN-g signature is based on the expression levels of the genes IDOl, CXCL10, CSCL9, HLA-DRA, STAT1, and IFN-g in the tumor microenvironment.
  • CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with the administration of the chemotherapy, and wherein the improvement in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone.
  • embodiment 103 wherein the determination of whether the cancer has a high expanded immunological signature is based on the expression levels of the genes CCL5, CD27, CD274, CD276, CD8A, CMKLR1, CXCL9, CXCR6, HLA-DRB1, HLA- DQA1, HLA-E, IDOl, LAG3, NKG7, PDCD1LG2, PSMB10, STAT1, and TIGIT in the tumor microenvironment.
  • invention 106 wherein the determination of whether the cancer is a hot tumor comprises comparing a cancer tissue sample to those characterized in FIG 7.
  • embodiment 106 wherein the determination of whether the cancer is a hot tumor comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I antigens available to initiate an effective immune response.
  • invention 106 wherein the determination of whether the cancer is a hot tumor comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class II antigens available to initiate an effective immune response.
  • embodiment 106 wherein the determination of whether the cancer is a hot tumor comprises assessing whether the cancer microenvironment has a sufficiently high degree of T cell and cytotoxic T cell infiltration.
  • the determination of whether the cancer is a hot tumor comprises assessing whether the cancer microenvironment has immune checkpoint activation selected from expression of programmed cell death protein 1 (PD-1) expression and cytotoxic T lymphocyte- associated antigen 4 (CTLA4) expression.
  • PD-1 programmed cell death protein 1
  • CTL4 cytotoxic T lymphocyte- associated antigen 4
  • invention 106 wherein the determination of whether the cancer is a hot tumor comprises assessing whether the cancer microenvironment has T-cell immunoglobulin mucin receptor 3 (TIM3) expression and lymphocyte activation gene 3 (LAG3) expression.
  • TIM3 T-cell immunoglobulin mucin receptor 3
  • LAG3 lymphocyte activation gene 3
  • embodiment 106 wherein the determination of whether the cancer is a hot tumor comprises assessing whether the cancer microenvironment has impaired T-cell functions.
  • embodiment 106 wherein the determination of whether the cancer is a hot tumor comprises assessing whether the cancer has genomic instability and the microenvironment has the presence of a pre-existing antitumor immune response.
  • CDK4/6 inhibitor is administered prior to administration of the chemotherapy, or alternatively, prior to and concurrently with the administration of the chemotherapy, and wherein the improvement in progression free survival or overall survival is in comparison to the progression free survival or overall survival based on administration of the chemotherapy alone.
  • the CDK4/6 inhibitor administered is Compound I, or a pharmaceutically acceptable salt thereof.
  • any of embodiments 97-123, wherein the ICD-inducing chemotherapy is selected from the group consisting of cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5- fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations of thereof.
  • the ICD-inducing chemotherapy is
  • any of embodiments 97-125 wherein the cancer is selected from the group consisting of triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, microsatellite instability- high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, and melanoma.
  • cHL codgkin lymphoma
  • PBMCL primary mediastinal B-cell lymphoma
  • urothelial carcinoma microsatellite instability- high (MSI-H) solid tumors
  • embodiment 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises comparing a cancer tissue sample to those characterized in FIG 7.
  • embodiment 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class I antigens available to initiate an effective immune response.
  • embodiment 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high level of major histocompatibility complex class II antigens available to initiate an effective immune response.
  • invention 128, wherein the determination of whether the cancer microenvironment has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer has a sufficiently high level of major histocompatibility complex class I and class II antigens available to initiate an effective immune response.
  • invention 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has a sufficiently high degree of T cell and cytotoxic T cell infiltration.
  • invention 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has immune checkpoint activation selected from expression of programmed cell death protein 1 (PD-1) expression and cytotoxic T lymphocyte- associated antigen 4 (CTLA4) expression.
  • PD-1 programmed cell death protein 1
  • CTL4 cytotoxic T lymphocyte- associated antigen 4
  • embodiment 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer microenvironment has T-cell immunoglobulin mucin receptor 3 (TIM3) expression and lymphocyte activation gene 3 (LAG3) expression.
  • TIM3 T-cell immunoglobulin mucin receptor 3
  • LAG3 lymphocyte activation gene 3
  • embodiment 128, wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing whether the cancer has genomic instability and the microenvironment has the presence of a pre-existing antitumor immune response.
  • invention 149 wherein the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises comparing a cancer tissue sample to those characterized in FIG 7.
  • embodiment 149 wherein the determination of whether the cancer has a surrounding microenvironment that is favorable to immune modulation comprises assessing the cancer according to the Galon immunoscore system.
  • embodiment 149 wherein the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises assessing whether the cancer microenvironment has low level of major histocompatibility complex class I antigens.
  • embodiment 149 wherein the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises assessing whether the cancer microenvironment has a low level of major histocompatibility complex class II antigens.
  • embodiment 149 wherein the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises assessing whether the cancer microenvironment has a low level of major histocompatibility complex class I and class II antigens.
  • embodiment 149 wherein the patient has a cancer that has low IFN-g expression in the tumor microenvironment, is not an IFN-g dominant class cancer, has a cancer with a low IFN-g signature or low expanded immune signature, or is PD-L1 negative.
  • the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises assessing whether the cancer microenvironment has a low degree of T cell and cytotoxic T cell infiltration.
  • invention 149 wherein the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises assessing whether the cancer microenvironment low programmed cell death protein 1 (PD- 1) expression and low cytotoxic T lymphocyte- associated antigen 4 (CTLA4) expression.
  • PD- 1 programmed cell death protein 1
  • CTL4 cytotoxic T lymphocyte- associated antigen 4
  • invention 149 wherein the determination of whether the cancer has a surrounding microenvironment that is not favorable to immune modulation comprises assessing whether the cancer microenvironment has low expression of T-cell immunoglobulin mucin receptor 3 (TIM3) and low expression of lymphocyte activation gene 3 (LAG3).
  • TIM3 T-cell immunoglobulin mucin receptor 3
  • LAG3 lymphocyte activation gene 3
  • any of embodiments 149-165 wherein the chemotherapy is selected from cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, oxaliplatin, methotrexate, mitroxantrone, gemcitabine, 5-fluorouracil (5-FU), bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, valrubicin, paclitaxel, cabazitaxel, docetaxel, topotecan, irinotecan, etoposide, carboplatin, cisplatin; bortezomib, vinblastine, vincristine, vindesine, vinorelbine, diaziquone, mechlorethamine, mitomycin C, fludarabine, cytosine arabinoside; and combinations of thereof.
  • the chemotherapy is selected from cyclophosphamide, trabectedin,
  • any of embodiments 149-166 wherein the cancer is selected from the group consisting of triple negative breast cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, classical Hodgkin lymphoma (cHL), bladder cancer, primary mediastinal B-cell lymphoma (PBMCL), urothelial carcinoma, microsatellite instability- high (MSI-H) solid tumors, mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, anal canal cancer, colorectal cancer, and melanoma.
  • cHL codgkin lymphoma
  • PBMCL primary mediastinal B-cell lymphoma
  • urothelial carcinoma microsatellite instability- high (MSI-H) solid tumors
  • embodiment 169 wherein the CDK4/6 inhibitor is administered in an administration schedule selected from the group consisting of at least once a week, at least once every two weeks, at least once every three weeks, at least once a month, and at least once every six months.
  • embodiment 171 wherein the CDK4/6 inhibitor and chemotherapy is administered in an administration schedule selected from the group consisting of at least once a week, at least once every two weeks, at least once every three weeks, at least once a month, at least once every six weeks, at least once every two months, at least once every three months, at least once every four months, at least once every five months, or at least once every six months.
  • an administration schedule selected from the group consisting of at least once a week, at least once every two weeks, at least once every three weeks, at least once a month, at least once every six weeks, at least once every two months, at least once every three months, at least once every four months, at least once every five months, or at least once every six months.
  • Trilaciclib Improves Overall and Progression Free Survival in Human Patients with Metastatic Triple Negative Breast Cancer Receiving Gemcitabine and Carboplatin.
  • Group 1 G/C therapy (Days 1 and 8 of 21 -day cycles);
  • Group 2 G/C therapy (Days 1 and 8) plus trilaciclib administered IV on Days 1 and 8 of 21-day cycles;
  • Group 3 G/C therapy (Days 2 and 9) plus trilaciclib administered IV on Days 1, 2, 8, and 9 of 21 -day cycles;
  • Trilaciclib was administered intravenously prior to GC infusion.
  • FIG. 1 An overview of the study is provided is Fig. 1.
  • TNBC metastatic TNBC
  • Hemoglobin levels must have been >9 0 g/dL in the absence of red blood cell (RBC) transfusion within 14 days prior to the first dose of trilaciclib, with an absolute neutrophil count (ANC) >1.5 x 10 9 /L and a platelet count >100 c 10 9 /L.
  • Patients were not eligible for inclusion if they had received >2 prior cytotoxic chemotherapy regimens for locally recurrent or mTNBC.
  • Chemotherapy administered in the neoadjuvant/adjuvant setting was considered a line of therapy when ⁇ 12 months had elapsed between the last treatment and disease recurrence.
  • Patients must have had an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate kidney and liver function, as determined by laboratory tests of serum creatinine ( ⁇ 1.5 mg/dL or creatinine clearance >60 mL/min), total bilirubin ⁇ 1.5 x upper limit of normal (ULN), and aspartate transaminase and alanine transaminase ⁇ 2.5 x ULN (or ⁇ 5 x ULN in the presence of liver metastases). With the exception of alopecia, resolution of non-hematological toxicities from prior treatment to grade ⁇ 1 was required.
  • the study was designed and conducted in compliance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonization.
  • the study protocol and all study-related materials were approved by the institutional review board or independent ethics committee of each investigational site.
  • Written informed consent was obtained from each patient prior to the initiation of study procedures.
  • Group 1 was given gemcitabine and carboplatin on days 1 and 8 (chemotherapy only)
  • group 2 was given trilaciclib before gemcitabine and carboplatin on days 1 and 8 (trilaciclib plus chemotherapy days 1 and 8)
  • group 3 was given trilaciclib only on days 1 and 8, and trilaciclib before gemcitabine and carboplatin on days 2 and 9 (trilaciclib days 1 and 8, trilaciclib plus chemotherapy days 2 and 9).
  • Group 3 was included to test the hypothesis that a second dose of trilaciclib before chemotherapy could increase the proportion of haemopoietic stem and progenitor cells in transient arrest at the time of chemotherapy administration, thereby improving myelosuppression outcomes.
  • Trilaciclib 240 mg/m 2 was given as an intravenous infusion over 30 min (allowable range 25-35 min) before gemcitabine and carboplatin treatment. No dose modifications of trilaciclib were allowed.
  • Treatment cycles occurred consecutively without interruption, except when necessary to manage toxicities. If dose reductions were required for chemotherapy they occurred in the following order: first, the gemcitabine dose was reduced from 1000 mg/m 2 to 800 mg/m 2 ; second, the carboplatin dose was reduced from AUC 2 pg x h/mL to AUC 1.5 pg x h/mL; third, either carboplatin or gemcitabine was discontinued and the other drug continued at the reduced dose; and finally, all study drugs were permanently discontinued. Dose reductions were allowed only once per cycle and were permanent.
  • Trilaciclib was administered only with GC therapy; if administration of chemotherapy was held or discontinued, trilaciclib was also held or discontinued. Study drug administration was continued until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator, whichever occurred first.
  • samples were collected for hematological laboratory assessment on days 1, 8, and 15 of each 21 -day cycle, regardless of treatment group. If the start of a subsequent cycle was delayed, laboratory assessments were done weekly (e.g., days 22, 29, 36, and so on) until the patient was able to start the next cycle or discontinued chemotherapy permanently. Unscheduled laboratory assessments were permitted as clinically indicated.
  • prophylactic growth factors including granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was not permitted during cycle 1. Otherwise, supportive care, including transfusions, was allowed as needed throughout the treatment period.
  • G-CSF granulocyte-colony stimulating factor
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • Platelets were transfused at a threshold of 10,000 per pL or less or a platelet count less than 50,000 per pL (100,000 per pL for central nervous system or ocular bleeding). Patients with a hemoglobin concentration of less than 8.0 g/dL or with symptomatic anemia could be treated with red blood cell transfusions at the investigator’s discretion. The percentage of patients receiving red blood cell trans-fusions and the number of red blood cell transfusions received over time was analyzed from on or after week 5 and from day 1 on study as part of a sensitivity analysis.
  • patient tumors were characterized as CDK4/6 independent, dependent, or indeterminate. Because triple-negative breast cancer is predominantly a functionally CDK4/6-independent disease, despite a genomic retinoblastoma inactivation rate of only 20%, these signatures were chosen to provide a more comprehensive analysis of CDK4/6 sensitivity.
  • PAM50 signature CDK4/6 independence correlates with basal-like tumors.
  • the remaining PAM50 signature groups (including HER2, normal-like, luminal A, and luminal B) are categorized as CDK4/6 indeterminate.
  • CDK4/6 dependence is closely correlated with luminal-androgen receptor tumors
  • Lehmann signature groups including basal-like and mesenchymal
  • Serious adverse events were defined as any untoward medical occurrence that, at any dose, results in death, a life-threatening event (i.e., the patient is at risk of death at the time of the event), inpatient admission to hospital or extension of current hospital admission, persistent or significant disability or incapacity, or a congenital anomaly or birth defect.
  • hematological parameters were assessed across multiple hematopoietic lineages, including the incidence and severity of hematological adverse events, laboratory values (absolute neutrophil count, hemoglobin concentration, and platelet count), supportive care interventions (red blood cell and platelet transfusions, use of G-CSF), and dose intensity and incidence of gemcitabine and carboplatin dose reductions. Full details of all parameters are described further below.
  • the primary objective was to assess the safety and tolerability of trilaciclib given with chemotherapy; specific focused endpoints were detailed in the statistical analysis plan, which defined the primary endpoints as duration of severe neutropenia (severe neutropenia is defined as CTCAE grade 4, absolute neutrophil count ⁇ 0.5 x 10 9 cells per L) in cycle 1 and occurrence of severe neutropenia during the treatment period.
  • Duration of severe neutropenia in cycle 1 was defined as the number of days from the date of the first absolute neutrophil count value of less than 0.5 x 10 9 cells per L to the date of the first absolute neutrophil count value of 0.5 c 10 9 cells per L or higher without observing absolute neutrophil count values of less than 0.5 x 10 9 cells per L until the end of the cycle.
  • Duration of severe neutropenia was set to zero days for patients who did not have severe neutropenia in cycle 1.
  • the occurrence of severe neutropenia was a binary endpoint defined as those having one or more readings of absolute neutrophil count below 0.5 c 10 9 cells per L during the treatment period. Both scheduled and unscheduled hematological laboratory results were included in the analysis of both primary endpoints.
  • a clinically relevant level of 0.5 x 10 9 cells per L was chosen for the primary analysis on the basis of the clinical link between severe neutropenia and an increased risk of infection and morbidity and mortality.
  • red blood cell transfusions Key secondary endpoints included the occurrence of red blood cell transfusions on or after week 5, G-CSF administrations, platelet transfusions, and overall survival.
  • Occurrence of red blood cell and platelet transfusions was a binary endpoint (yes or no) and the total number of transfusions was a count endpoint (number of transfusions with a unique start date).
  • Overall survival was calculated as the time (in months) from the date of randomization to the date of death due to any cause.
  • Supportive secondary antitumor activity endpoints are the proportion of patients who achieved an objective response (defined as a confirmed complete or partial response), duration of response, and progression-free survival.
  • the clinical benefit rate was calculated using data from any patient who had a complete or partial response at any time after treatment or stable disease for 24 weeks or longer; if a patient did not have a complete or partial response and duration of stable disease was indeterminate, they were considered not evaluable.
  • Progression-free survival was defined as the time (in months) from the date of randomization until the date of radiologically confirmed disease progression or death due to any cause, whichever came first.
  • Specific endpoints across the trilaciclib development program and prespecified in the statistical analysis plan was used to show superiority of group 3 over group 1 with 90% power for at least one primary endpoint (either duration of severe neutropenia in cycle 1 or occurrence of severe neutropenia).
  • An equally-weighted Bonferroni procedure was used to maintain the overall two-sided type I error rate at 0.05 and calculated that 64 patients (32 per group) were needed to detect a 3 day reduction of duration of severe neutropenia in cycle 1 with a common SD of 2.5 days or a 41 percentage point absolute reduction in the proportion of patients with severe neutropenia (i.e., 45% for the group 1 and 4% for group 3). Assuming a 5% attrition rate, we needed 102 patients in total (34 per group).
  • a non-parametric analysis of covariance was used to assess treatment group differences for duration of severe neutropenia in cycle 1 using stratification factors and treatment as fixed effects, with baseline absolute neutrophil count value as a covariate.
  • a modified Poisson regression model was used to assess the treatment effect.
  • the model included the same fixed terms as used for duration of severe neutropenia, with baseline absolute neutrophil count as the covariate for severe neutropenia and G-CSF administration analyses, baseline hemoglobin concentration as the covariate for red blood cell transfusion analysis and baseline platelet count as the covariate for platelet transfusion analysis. Duration of treatment (in weeks) was adjusted in this model.
  • Treatment group differences in objective response were analyzed by use of an exact Cochran-Mantel-Haenszel method accounting for the stratification factors.
  • the 95% CIs for the proportion of patients who achieved an objective response was calculated using the exact Clopper- Pearson method.
  • time-to-event variables such as duration of response, progression-free survival, and overall survival
  • Kaplan-Meier method was used to estimate the median time and its 95% Cl.
  • Treatment group differences were tested using the stratified log-rank test to account for the stratification factors.
  • Hazard ratios (HRs) and their associated 95% CIs were calculated from the Cox proportional hazards model, with treatment and stratification factors as fixed effects.
  • the statistical analysis plan prespecified the primary statistical comparison for the primary and key secondary endpoints to be between group 3 and group 1, and prespecified secondary comparisons were to be between group 2 and group 1, and between the combined trilaciclib groups and group 1.
  • Activity analyses were conducted using the intention-to-treat (ITT) population on the basis of the assigned treatment for myelosuppression and antitumor activity endpoints, with the exception of tumor response endpoints (objective response and clinical benefit), which were analyzed in patients who received at least one dose of study drug, had measurable target lesions at the baseline tumor assessment, and either had at least one tumor assessment after treatment (or no tumor assessment after treatment but had clinical progression as noted by the investigator) or had died due to disease progression before their first tumor scan after treatment (response evaluable population). Duration of survival follow-up was calculated from date of randomization to date of death or the last contact date as of activity data cutoff, which is specified throughout. Safety analyses included all patients who received at least one dose of study medication. The stratification factors (number of previous lines of systemic therapy and liver involvement) were adjusted in statistical models.
  • Prespecified subgroup analyses was performed for progression-free survival and overall survival to assess consistency of treatment effect (i.e., age group, race, liver involvement, country, ECOG performance status, number of previous lines of therapy, BRCA classification, and histological triple-negative breast cancer classification).
  • a post-hoc analysis of antitumor activity endpoints was performed based on the overall median number of cycles patients received during the study. The analysis was done in patients grouped according to whether they had received 1-7 cycles or more than 7 cycles.
  • Median duration of treatment was 101 days (IQR 63-203 [median of four cycles]) in group 1, 161 days (77-287 [median of seven cycles]) in group 2, and 168 days (91-217 [median of eight cycles]) in group 3.
  • the median cumulative dose of carboplatin was AUC 15 pg c h/mL (IQR 8- 28) in group 1 versus AUC 24 pg x h/mL (IQR 10-40) in group 2 and AUC 22 pg x h/mL (IQR 15-34) in group 3.
  • the median cumulative dose increased to 7306.2 mg/m 2 (IQR 4020.1-15138.9) in group 1, to 12000.0 mg/m 2 (IQR 5029.4-21882.7) in group 2 and 11800.1 mg/m 2 (IQR 7000.0-17446.9) in group 3.
  • IQR 4020.1-15138.9 the median cumulative dose increased to 7306.2 mg/m 2
  • IQR 5029.4-21882.7 the median cumulative dose increased to 7306.2 mg/m 2
  • IQR 5029.4-21882.7 IQR 5029.4-21882.7
  • 11800.1 mg/m 2 IQR 7000.0-17446.9
  • RNA signatures 1) CDK4/6 independent and variable CDK4/6 dependent buckets defined by PAM50 (see Prat et al., Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med. 2015; 13: 303. doi: 10.1186/sl2916-015-0540-z, incorporated herein by reference); and 2) CDK4/6 dependent and variable CDK4/6 dependent buckets defined by Lehmann (see Lehmann et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121 :2750-67. doi: 10.1172/JCI45014, incorporated herein by reference) (Table 6).
  • Results from a post-hoc analysis of antitumor effects according to median number of cycles (1-7 vs >7 cycles) are provided in Table 9. Across all three treatment groups, the proportion of patients who achieved an objective response was higher among those who received more than seven treatment cycles compared with those receiving seven cycles or fewer.
  • Example 1 Tumor samples from patients participating in the clinical trial described in Example 1 where assayed by Q 2 Solutions (Morrisville, NC) to determine their Ayers Immune Scores according to Ayers et al., IFN-y-related mRNA Profile Predicts Clinical Response to PD-1 Blockade, J Clin Invest. 2017127(8)2930-2940.
  • the data was processed using RNA Access, and FPKM normalization prior to log 10 transformation and averaging was performed.
  • Fig. 8 A shows the distribution of the Ayers’ IFN-g Signature across the 89 samples tested.
  • Fig. 8B shows the distribution of the Ayers’ Expanded Immune Signature across the 89 samples tested. Survival and response rates between treatment groups within pre-defmed immune response groups were determined using a series of pair-wise, two-group tests based on the data derived in the G1T28-04 clinical trial described in Example 1. Additionally, examination of differences in survival and response rates between different immune response categories within a single treatment group were analyzed. Results are provided in Table 10 and Table 11.
  • Kaplan-Meier curves were generated to visualize the overall survival and progression free survival among groups (see Fig. 8C-8F and 9A-9D).
  • the groups are divided as follows: Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and with respect to the Kaplan-Meier curve, Group 4 (Group 2 + Group 3).
  • RNAseq data procurement the data was cleaned and homogenized by reconciling gene and sample names across data sources. Batch correction was performed in order to render the clinical trial-generated data and TCGA data comparable to ensure valid classification.
  • samples in the resulting TCGA expression data were randomly down-sampled to more closely reflect the abundance of PAM50 classes within the clinical trial data (previously derived, see Example 1, Table 7).
  • Per-gene linear regression modelling on log2 transformed, upper-quartile normalized expressions was used to estimate batch effects in the clinical trial data. These estimated batch effects were then removed from the expressions of clinical trial samples via arithmetic subtraction, resulting in a mean shift towards the TCGA samples.
  • Kaplan-Meier curves were generated to visualize the overall survival and progression free survival among groups (see Fig. 10A-10D).
  • the groups are divided as follows: Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a 21 day cycle), and Group 3 (gemcitabine + carboplatin on days 2 and 9 + trilaciclib on days 1, 2, 8, and 9 in a 21 -day cycle), and with respect to the Kaplan-Meier curved, Group 4 (Group 2 + Group 3).
  • Example 1 Patient tumors from the G1T28-04 clinical trial described in Example 1 were characterized based on PD-L1 expression scored as negative or positive if ⁇ 1% or >1% of the total tumor area contained PD-Ll-labelled immune cells, respectively, using the Ventana SP142 assay. Association of PD-L1 expression with antitumor efficacy was assessed using proportional hazards regression. The groups are divided as follows: Group 1 (gemcitabine + carboplatin only on days 1 and 8 in a 21 -day cycles), Group 2 (gemcitabine + carboplatin + trilaciclib on days 1 and 8 in a
  • trilaciclib 240 mg/m2 diluted in 250 mL D5W or sodium chloride solution 0.9%) or placebo (250 mL of D5W or sodium chloride solution 0.9%) administered IV once daily on days 1 to 3 of a 21 -day cycle of each etoposide/carboplatin/atezolizumab (E/P/ A) therapy cycle (up to 4 cycles in total).
  • Atezolizumab (1200 mg) in 250 mL sodium chloride solution 0.9% was administered as an IV infusion on day 1 of each 21 -day cycle in both the induction and maintenance phases. Atezolizumab was infused over 60 minutes for the first administration and, if tolerated, all subsequent infusions were delivered over 30 minutes. Atezolizumab was administered following the completion of administration of Compound I or placebo, etoposide, and carboplatin.
  • T-cell receptor b sequences was determined by the differential abundance analysis of T-cell receptor b sequences in whole blood from patients at after induction and prior to starting maintenance versus baseline.
  • trilaciclib significantly increased the number and fraction of newly expanded clones demonstrating that the addition of trilaciclib to the etoposide, carboplatin, atezolizumab treatment regimen enhances the T-cell mediated anti-tumor response.

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Abstract

L'invention concerne un procédé pour augmenter la survie sans progression ou la survie globale d'un patient atteint d'un cancer comprenant les étapes consistant à : déterminer si le cancer présente un microenvironnement environnant qui est favorable à la modulation immunitaire; déterminer si le régime de chimiothérapie induit la mort cellulaire immunogène, et si les deux sont oui, administrer une quantité efficace d'un inhibiteur de CDK4/6 choisi parmi les composés I, II, III, IV ou V ou un sel pharmaceutiquement acceptable de ceux-ci, l'inhibiteur de CDK4/6 étant administré avant l'administration de la chimiothérapie ou éventuellement avant et simultanément à une chimiothérapie; et l'augmentation de la survie sans progression ou de la survie globale étant par rapport à la survie sans progression ou à la survie globale sur la base de l'administration de la chimiothérapie seule, soit sur la base de la littérature, soit d'une preuve autrement disponible au public, d'un comparatif lors d'essais précliniques ou cliniques ou d'autres moyens acceptés par l'homme du métier.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022258002A1 (fr) * 2021-06-10 2022-12-15 上海岸阔医药科技有限公司 Composé et procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie
WO2023278860A1 (fr) * 2021-07-01 2023-01-05 G1 Therapeutics, Inc. Polythérapies chez des patients atteints de cancers surexprimés trop-2 avancés et/ou métastasiques
WO2023064913A1 (fr) * 2021-10-14 2023-04-20 Wisconsin Alumni Research Foundation K17 utilisée en tant que biomarqueur pour la réponse tumorale à l'immunothérapie

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2906166C (fr) * 2013-03-15 2023-03-14 G1 Therapeutics, Inc. Traitements epargnant hspc pour la proliferation cellulaire anormale rb positive
CN115698014A (zh) 2020-05-19 2023-02-03 G1治疗公司 用于治疗医学病症的细胞周期蛋白依赖性激酶抑制化合物
CN115019880B (zh) * 2022-05-05 2024-01-09 中山大学附属第一医院 一种肝癌预后模型及其构建方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160220569A1 (en) * 2015-02-03 2016-08-04 G1 Therapeutics, Inc. CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy
WO2018089518A1 (fr) * 2016-11-08 2018-05-17 Dana-Farber Cancer Institute, Inc. Compositions et méthodes de modulation d'immunité anti-tumorale
WO2018106729A1 (fr) * 2016-12-05 2018-06-14 G1 Therapeutics, Inc. Préservation de la réponse immunitaire lors de régimes chimiothérapeutiques
WO2019108589A1 (fr) * 2017-11-30 2019-06-06 Beth Israel Deaconess Medical Center, Inc. Compositions et méthodes pour le traitement du cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2906166C (fr) * 2013-03-15 2023-03-14 G1 Therapeutics, Inc. Traitements epargnant hspc pour la proliferation cellulaire anormale rb positive
CN110325191A (zh) * 2017-02-22 2019-10-11 G1治疗公司 以较少的副作用治疗egfr-驱动的癌症

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160220569A1 (en) * 2015-02-03 2016-08-04 G1 Therapeutics, Inc. CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy
WO2018089518A1 (fr) * 2016-11-08 2018-05-17 Dana-Farber Cancer Institute, Inc. Compositions et méthodes de modulation d'immunité anti-tumorale
WO2018106729A1 (fr) * 2016-12-05 2018-06-14 G1 Therapeutics, Inc. Préservation de la réponse immunitaire lors de régimes chimiothérapeutiques
WO2019108589A1 (fr) * 2017-11-30 2019-06-06 Beth Israel Deaconess Medical Center, Inc. Compositions et méthodes pour le traitement du cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JEFF MACDONALD: "G1 Therapeutics Announces Positive Myelopreservation Data from Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of Trilaciclib in Combination with Chemotherapy/Tecentriq in First-Line Small Cell Lung Cancer", G1 THERAPEUTICS, 26 November 2018 (2018-11-26), pages 1, XP055776008, Retrieved from the Internet <URL:http://investor.g1therapeutics.com/news-releases/news-release-details/g1-therapeutics-announces-positive-myelopreservation-data> *
See also references of EP3986410A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022258002A1 (fr) * 2021-06-10 2022-12-15 上海岸阔医药科技有限公司 Composé et procédé de traitement d'effets secondaires gastro-intestinaux associés à la chimiothérapie
WO2023278860A1 (fr) * 2021-07-01 2023-01-05 G1 Therapeutics, Inc. Polythérapies chez des patients atteints de cancers surexprimés trop-2 avancés et/ou métastasiques
WO2023064913A1 (fr) * 2021-10-14 2023-04-20 Wisconsin Alumni Research Foundation K17 utilisée en tant que biomarqueur pour la réponse tumorale à l'immunothérapie

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